rs768071555

Positions:

chr21-33588560-T-G

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. 12/20 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. 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: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]

DONSON links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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
DONSON	NM_017613.4 linkuse as main transcript	c.82A>C	p.Ser28Arg	missense_variant	1/10	ENST00000303071.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DONSON	ENST00000303071.10 linkuse as main transcript	c.82A>C	p.Ser28Arg	missense_variant	1/10	1	NM_017613.4	P1	Q9NYP3-1

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

GnomAD3 exomes

AF:

0.00171

AC:

AN:

2340

Hom.:

AF XY:

0.00140

AC XY:

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.:

Cov.:

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.:

Cov.:

AF XY:

0.000889

AC XY:

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.:

Bravo

AF:

0.00146

ExAC

AF:

0.000901

AC:

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 submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	DONSON: PM2:Supporting, BS3:Supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 13, 2022	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). 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. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2021

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. -

Microcephaly-micromelia syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Mar 05, 2018

- -

Microcephaly, short stature, and limb abnormalities

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Mar 31, 2022

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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.0038

T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Pathogenic

0.85

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over