chr21-33579447-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_017613.4(DONSON):c.1466A>C(p.Lys489Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000928 in 1,614,182 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K489R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00093 ( 2 hom. )

Consequence

DONSON
NM_017613.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:1B:4

Conservation

PhyloP100: -2.70

Publications

8 publications found

Variant links:

Genes affected

DONSON (HGNC:2993): (DNA replication fork stabilization factor DONSON) This gene lies downstream of the SON gene and spans 10 kb on chromosome 21. The function of this gene is unknown. [provided by RefSeq, Jul 2008]

DONSON Gene-Disease associations (from GenCC):

microcephaly, short stature, and limb abnormalities
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

DONSON links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008210868).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000919 (140/152320) while in subpopulation AMR AF = 0.00176 (27/15302). AF 95% confidence interval is 0.00124. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017613.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DONSON	NM_017613.4	MANE Select	c.1466A>C	p.Lys489Thr	missense	Exon 9 of 10	NP_060083.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DONSON	ENST00000303071.10	TSL:1 MANE Select	c.1466A>C	p.Lys489Thr	missense	Exon 9 of 10	ENSP00000307143.4
DONSON	ENST00000442660.5	TSL:1	n.*495A>C		non_coding_transcript_exon	Exon 7 of 8	ENSP00000408788.1
DONSON	ENST00000444517.5	TSL:1	n.*103A>C		non_coding_transcript_exon	Exon 4 of 5	ENSP00000392405.1

Frequencies

GnomAD3 genomes

AF:

0.000926

AC:

141

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000974

AC:

245

AN:

251470

AF XY:

0.00104

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.00724

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000888

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000929

AC:

1358

AN:

1461862

Hom.:

Cov.:

AF XY:

0.000985

AC XY:

716

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.00107

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00685

AC:

179

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39692

South Asian (SAS)

AF:

0.000568

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000841

AC:

935

AN:

1111996

Other (OTH)

AF:

0.00166

AC:

100

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

151

226

302

377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000919

AC:

140

AN:

152320

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41574

American (AMR)

AF:

0.00176

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.000829

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

68024

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000361

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.000988

AC:

120

EpiCase

AF:

0.000927

EpiControl

AF:

0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly, short stature, and limb abnormalities

Pathogenic:3

Nov 16, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 10, 2021

New York Genome Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with microcephaly, short stature, and limb abnormalities (MIM#617604) and microcephaly-micromelia syndrome (MIM#251230). (I) 0106 - This gene is associated with autosomal recessive disease. However there has been one previous report of an individual with femoral facial syndrome who was only heterozygous for one DONSON variant (PMID: 31407851). (I) 0200 - Variant is predicted to result in a missense amino acid change from lysine to threonine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (264 heterozygotes, 1 homozygote). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (220 heterozygotes, 2 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. However a variant with a lower Grantham score, p.(Lys489Arg), has been reported as benign once by a clinical laboratory in ClinVar. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in eleven individuals with DONSON-related conditions and in at least seven it was observed on an ancestral haplotype, in cis with two other DONSON variants, p.(Ser28Arg) and c.786-33A>G, variants that are not considered to be pathogenic (ClinVar, PMID: 28191891). This variant has also previously been classified as a VUS or benign by clinical laboratories in ClinVar. (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Western blot and immunoblot studies have shown this variant causes reduced DONSON protein levels (PMID: 28191891). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

not provided

Benign:2

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DONSON: BP4

Microcephaly

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PS3,PM2,PM3

Inborn genetic diseases

Pathogenic:1

Sep 08, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.82A>C (p.S28R) alteration is located in exon 1 (coding exon 1) of the DONSON gene. This alteration results from an A to C substitution at nucleotide position 82, causing the serine (S) at amino acid position 28 to be replaced by an arginine (R). The c.1466A>C (p.K489T) alteration is located in exon 9 (coding exon 9) of the DONSON gene. This alteration results from an A to C substitution at nucleotide position 1466, causing the lysine (K) at amino acid position 489 to be replaced by a threonine (T). The p.S28R and p.K489T alterations have been observed to be linked in cis and form a haplotype which also includes an intronic c.786-33A>G change (Reynolds, 2017). Based on the available evidence, the DONSON c.[82A>C;1466A>C] (p.[S28R;K489T]) haplotype is classified as pathogenic._x000D_ _x000D_ VUS if seen without c.82A>C Based on data from gnomAD, the C allele has an overall frequency of 0.09% (266/282866) total alleles studied. The highest observed frequency was 0.72% (75/10370) of Ashkenazi Jewish alleles. This haplotype including p.S28R, p.K489T, and c.786-33A>G was detected in the heterozygous state in trans with truncating variants in five unrelated patients with microcephalic dwarfism (Reynolds, 2017). The p.S28R and p.K489T variants were both identified in the homozygous state in an individual from a consanguineous family with spondylo-epi-metaphyseal dysplasia (SEMD) who had many additional homozygous variants in other genes as well (Guo, 2017). The p.S28 and p.K489 amino acids are not well conserved in available vertebrate species. Of the three variants in the common haplotype, only p.K489T was found to have a negative effect in functional studies. Functional analysis demonstrated the p.K489T alteration reduced protein levels and was unable to complement the loss of endogenous DONSON during replication fork stalling (Reynolds, 2017). The p.S28R and p.K489T alterations are predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

See cases

Pathogenic:1

Apr 26, 2021

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3_moderate;PM2_supporting;PM3_moderate;PP5_supporting;BP4_supporting

Microcephaly-micromelia syndrome;C4539873:Microcephaly, short stature, and limb abnormalities

Pathogenic:1

May 01, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Microcephaly-micromelia syndrome

Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Jun 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DONSON c.1466A>C (p.Lys489Thr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00097 in 251470 control chromosomes, predominantly at a frequency of 0.0072 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in DONSON causing Microcephaly, Short Stature, And Limb Abnormalities phenotype. c.1466A>C has been reported in the literature in individuals affected with Microcephaly, Short Stature, And Limb Abnormalities (Chong_2015, Reynolds_2017,Vaseghi_2023). In addition, this variant was found in a haplotype defined by 3 co-segregating variants (c.82A>C:p.Ser28Arg; c.78633A>G; c.1466A>C:p.Lys489Thr) (Reynolds_2017). These reports do not provide unequivocal conclusions about association of the variant with Microcephaly, Short Stature, And Limb Abnormalities. At least one publication reports experimental evidence evaluating an impact on protein function (Reynolds_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27040692, 28191891, 37823350). ClinVar contains an entry for this variant (Variation ID: 431445). Based on the evidence outlined above, the variant was classified as likely benign.

DONSON-related disorder

Benign:1

Jul 18, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.036

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.017

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.60

M_CAP

Benign

0.0070

MetaRNN

Benign

0.0082

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.9

PhyloP100

-2.7

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.4

REVEL

Benign

0.11

Sift

Benign

0.073

Sift4G

Benign

0.10

Polyphen

0.55

Vest4

0.20

MVP

0.16

MPC

0.18

ClinPred

0.030

GERP RS

-9.3

Varity_R

0.047

gMVP

0.49

Mutation Taster

=88/12

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over