rs768071555

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_017613.4(DONSON):c.82A>C(p.Ser28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000905 in 1,252,790 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. S28I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00090 ( 1 hom. )

Consequence

DONSON
NM_017613.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:2O:1

Conservation

PhyloP100: 1.53

Publications

6 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:

ENSG00000249209 (HGNC:):

ENSG00000249209 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038296878).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000922 (140/151876) while in subpopulation AMR AF = 0.00177 (27/15260). AF 95% confidence interval is 0.00125. There are 0 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.82A>C	p.Ser28Arg	missense	Exon 1 of 10	NP_060083.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DONSON	ENST00000303071.10	TSL:1 MANE Select	c.82A>C	p.Ser28Arg	missense	Exon 1 of 10	ENSP00000307143.4
ENSG00000249209	ENST00000429238.2	TSL:5	c.442-2379A>C		intron	N/A	ENSP00000394107.2
DONSON	ENST00000303113.10	TSL:5	c.82A>C	p.Ser28Arg	missense	Exon 1 of 11	ENSP00000304716.3

Frequencies

GnomAD3 genomes

AF:

0.000929

AC:

141

AN:

151768

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00750

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.000191

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.00171

AC:

AN:

2340

AF XY:

0.00140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00602

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00197

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.000903

AC:

994

AN:

1100914

Hom.:

Cov.:

AF XY:

0.000963

AC XY:

505

AN XY:

524226

show subpopulations

African (AFR)

AF:

0.000263

AC:

AN:

22844

American (AMR)

AF:

0.00216

AC:

AN:

8794

Ashkenazi Jewish (ASJ)

AF:

0.00644

AC:

AN:

14606

East Asian (EAS)

AF:

0.00

AC:

AN:

26360

South Asian (SAS)

AF:

0.000392

AC:

AN:

28086

European-Finnish (FIN)

AF:

0.000312

AC:

AN:

22402

Middle Eastern (MID)

AF:

0.00371

AC:

AN:

2964

European-Non Finnish (NFE)

AF:

0.000828

AC:

771

AN:

930710

Other (OTH)

AF:

0.00170

AC:

AN:

44148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

125

187

250

312

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:

0.000922

AC:

140

AN:

151876

Hom.:

Cov.:

AF XY:

0.000889

AC XY:

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41480

American (AMR)

AF:

0.00177

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00750

AC:

AN:

3468

East Asian (EAS)

AF:

0.000581

AC:

AN:

5162

South Asian (SAS)

AF:

0.000828

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000191

AC:

AN:

10488

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

67878

Other (OTH)

AF:

0.00285

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000635

Hom.:

Bravo

AF:

0.00146

ExAC

AF:

0.000901

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 28 of the DONSON protein (p.Ser28Arg). This variant is present in population databases (rs768071555, gnomAD 0.8%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with microcephalic dwarfism (PMID: 28191891) or clinical features of this condition (PMID: 37644014, 37823350). It has been reported as part of a shared haplotype with p.Lys489Thr and c.786-33A>G variants in affected individuals (PMID: 28191891). ClinVar contains an entry for this variant (Variation ID: 431446). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DONSON protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DONSON: PM2:Supporting, BS3:Supporting

Microcephaly-micromelia syndrome

Uncertain:1Other: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

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 09-14-2021 by Invitae. GenomeConnect-InvitaePIN assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Microcephaly, short stature, and limb abnormalities

Benign:2

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely benign

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 Likely benign. 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 serine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (141 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (4 heterozygotes, 0 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. (I) 0806 - This variant has moderate previous evidence of being benign in unrelated individuals. This variant has been observed on an ancetral haplotype and in cis with another missense variant p.(Lys489Thr) that is considered pathogenic in at least seven unrelated individuals (ClinVar, PMID: 28191891). This variant has also been classified as pathogenic and as a VUS by clinical laboratories in ClinVar. (SB) 1004 - This variant has moderate functional evidence supporting normal protein function. Western blot and immunoblot studies have shown this variant does not reduce the levels of DONSON protein (PMID: 28191891). This variant has also been shown to rescue spontaneous replication fork stalling observed on DONSON depletion (PMID: 28191891). (SB) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Jun 16, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

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.1466A>C Based on data from gnomAD, the C allele has an overall frequency of 0.08% (25/33238) total alleles studied. The highest observed frequency was 0.66% (3/452) 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. The p.S28R alteration failed to reduce protein levels and was able to complement 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.

not specified

Uncertain:1

Jun 09, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: DONSON c.82A>C (p.Ser28Arg) 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 0.0017 in 2340 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.82A>C has been reported in the literature in individuals affected with Microcephaly, Short Stature, And Limb Abnormalities (Reynolds_2017, AlAbdi_2023, Vaseghi_2023). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function and shows no significant effect (Reynolds_2017). The following publications have been ascertained in the context of this evaluation (PMID: 37644014, 28191891, 37823350). ClinVar contains an entry for this variant (Variation ID: 431446). Based on the evidence outlined above, the variant was classified as uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0070

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.73

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

1.5

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.43

REVEL

Benign

0.065

Sift

Benign

0.38

Sift4G

Benign

0.37

Polyphen

0.0010

Vest4

0.085

MutPred

0.30

Loss of phosphorylation at S28 (P = 6e-04)

MVP

0.13

MPC

0.096

ClinPred

0.034

GERP RS

1.5

PromoterAI

0.0062

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.049

gMVP

0.40

Mutation Taster

=91/9

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