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rs768071555

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1PM2BP4_Strong

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. 11/19 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

1
2
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:1

Conservation

PhyloP100: 1.53
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 Uncertain_significance.

PM1
In a modified_residue Phosphoserine (size 0) in uniprot entity DONS_HUMAN
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0038296878).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DONSONNM_017613.4 linkuse as main transcriptc.82A>C p.Ser28Arg missense_variant 1/10 ENST00000303071.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DONSONENST00000303071.10 linkuse as main transcriptc.82A>C p.Ser28Arg missense_variant 1/101 NM_017613.4 P1Q9NYP3-1

Frequencies

GnomAD3 genomes
AF:
0.000929
AC:
141
AN:
151768
Hom.:
0
Cov.:
33
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
GnomAD3 exomes
AF:
0.00171
AC:
4
AN:
2340
Hom.:
0
AF XY:
0.00140
AC XY:
2
AN XY:
1426
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 SAS 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.:
1
Cov.:
31
AF XY:
0.000963
AC XY:
505
AN XY:
524226
show subpopulations
Gnomad4 AFR exome
AF:
0.000263
Gnomad4 AMR exome
AF:
0.00216
Gnomad4 ASJ exome
AF:
0.00644
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000392
Gnomad4 FIN exome
AF:
0.000312
Gnomad4 NFE exome
AF:
0.000828
Gnomad4 OTH exome
AF:
0.00170
GnomAD4 genome
AF:
0.000922
AC:
140
AN:
151876
Hom.:
0
Cov.:
33
AF XY:
0.000889
AC XY:
66
AN XY:
74246
show subpopulations
Gnomad4 AFR
AF:
0.0000723
Gnomad4 AMR
AF:
0.00177
Gnomad4 ASJ
AF:
0.00750
Gnomad4 EAS
AF:
0.000581
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.000191
Gnomad4 NFE
AF:
0.00100
Gnomad4 OTH
AF:
0.00285
Alfa
AF:
0.000635
Hom.:
0
Bravo
AF:
0.00146
ExAC
AF:
0.000901
AC:
12

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 13, 2022This 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). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 431446). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DONSON protein function. 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. -
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2022DONSON: PM2:Supporting, BS3:Supporting -
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. 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. -
Microcephaly-micromelia syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenomic Research Center, Shahid Beheshti University of Medical SciencesMar 05, 2018- -
Microcephaly, short stature, and limb abnormalities Benign:1
Likely benign, 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 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 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.24
Cadd
Benign
15
Dann
Uncertain
0.98
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.47
FATHMM_MKL
Benign
0.48
N
LIST_S2
Benign
0.73
T;T;T;T
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.0038
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
-0.43
N;N;N;N
REVEL
Benign
0.065
Sift
Benign
0.38
T;T;T;T
Sift4G
Benign
0.37
T;T;T;T
Polyphen
0.0010
B;.;B;.
Vest4
0.085
MutPred
0.30
Loss of phosphorylation at S28 (P = 6e-04);Loss of phosphorylation at S28 (P = 6e-04);Loss of phosphorylation at S28 (P = 6e-04);Loss of phosphorylation at S28 (P = 6e-04);
MVP
0.13
MPC
0.096
ClinPred
0.034
T
GERP RS
1.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.049
gMVP
0.40

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: rs768071555; hg19: chr21-34960866; COSMIC: COSV51678669; COSMIC: COSV51678669; API