chr21-33579447-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The ENST00000303071.10(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. 14/20 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
ENST00000303071.10 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2B:3

Conservation

PhyloP100: -2.70
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.008210868).
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DONSONNM_017613.4 linkuse as main transcriptc.1466A>C p.Lys489Thr missense_variant 9/10 ENST00000303071.10 NP_060083.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DONSONENST00000303071.10 linkuse as main transcriptc.1466A>C p.Lys489Thr missense_variant 9/101 NM_017613.4 ENSP00000307143 P1Q9NYP3-1

Frequencies

GnomAD3 genomes
AF:
0.000926
AC:
141
AN:
152202
Hom.:
0
Cov.:
32
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
GnomAD3 exomes
AF:
0.000974
AC:
245
AN:
251470
Hom.:
1
AF XY:
0.00104
AC XY:
142
AN XY:
135912
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 SAS exome
AF:
0.000621
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.:
2
Cov.:
31
AF XY:
0.000985
AC XY:
716
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.000388
Gnomad4 AMR exome
AF:
0.00107
Gnomad4 ASJ exome
AF:
0.00685
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.000568
Gnomad4 FIN exome
AF:
0.000187
Gnomad4 NFE exome
AF:
0.000841
Gnomad4 OTH exome
AF:
0.00166
GnomAD4 genome
AF:
0.000919
AC:
140
AN:
152320
Hom.:
0
Cov.:
32
AF XY:
0.000886
AC XY:
66
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.00176
Gnomad4 ASJ
AF:
0.00749
Gnomad4 EAS
AF:
0.000578
Gnomad4 SAS
AF:
0.000829
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.00100
Gnomad4 OTH
AF:
0.00284
Alfa
AF:
0.000463
Hom.:
0
Bravo
AF:
0.00147
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00186
AC:
16
ExAC
AF:
0.000988
AC:
120
EpiCase
AF:
0.000927
EpiControl
AF:
0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Microcephaly, short stature, and limb abnormalities Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics Munich, Klinikum Rechts Der Isar, TU MünchenNov 16, 2017- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMar 31, 2022Based 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 -
Likely pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterDec 10, 2021- -
not provided Benign:2
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2023DONSON: BP4 -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Microcephaly Pathogenic:1
Likely pathogenic, criteria provided, single submitterresearchAl Jalila Children’s Genomics Center, Al Jalila Childrens Speciality HospitalOct 04, 2024PS3,PM2,PM3 -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 08, 2021The 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
Likely pathogenic, criteria provided, single submitterclinical testingGenetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc TauliApr 26, 2021PS3_moderate;PM2_supporting;PM3_moderate;PP5_supporting;BP4_supporting -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 31, 2024Variant summary: DONSON c.1466A>C (p.Lys489Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00097 in 251470 control chromosomes in the gnomAD database, including one homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in DONSON causing Microcephaly, Short Stature, And Limb Abnormalities, allowing no conclusion about variant significance. c.1466A>C has been reported in the literature in individuals affected with Microcephaly, Short Stature, And Limb Abnormalities (Chong_2015, Reynolds_2017). 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). ClinVar contains an entry for this variant (Variation ID: 431445). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Microcephaly-micromelia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMar 05, 2018- -
DONSON-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 18, 2024This 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 v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.15
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
0.036
DANN
Benign
0.96
DEOGEN2
Benign
0.017
.;T
Eigen
Benign
-0.97
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.23
N
LIST_S2
Benign
0.60
T;T
M_CAP
Benign
0.0070
T
MetaRNN
Benign
0.0082
T;T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
1.9
.;L
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-2.4
N;N
REVEL
Benign
0.11
Sift
Benign
0.073
T;T
Sift4G
Benign
0.10
T;T
Polyphen
0.55
P;P
Vest4
0.20
MVP
0.16
MPC
0.18
ClinPred
0.030
T
GERP RS
-9.3
Varity_R
0.047
gMVP
0.49

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146664036; hg19: chr21-34951753; API