rs768071555

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PS3BP4_StrongBS1

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). ClinVar reports functional evidence for this variant: "SCV000742269: "The p.S28R alteration failed to reduce protein levels and was able to complement loss of endogenous DONSON during replication fork stalling (Reynolds, 2017)."". 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:3O: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: Ambry Genetics, Labcorp Genetics (formerly Invitae)

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 -4 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000742269: "The p.S28R alteration failed to reduce protein levels and was able to complement loss of endogenous DONSON during replication fork stalling (Reynolds, 2017)."

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.

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

Sel.	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	Q9NYP3-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DONSON	ENST00000303071.10	TSL:1 MANE Select	c.82A>C	p.Ser28Arg	missense	Exon 1 of 10	ENSP00000307143.4	Q9NYP3-1
ENSG00000249209	ENST00000429238.2	TSL:5	c.442-2379A>C		intron	N/A	ENSP00000394107.2	H7C0C1
DONSON	ENST00000966267.1		c.82A>C	p.Ser28Arg	missense	Exon 1 of 11	ENSP00000636326.1

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

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microcephaly, short stature, and limb abnormalities (2)

not provided (2)

Inborn genetic diseases (1)

Microcephaly-micromelia syndrome (2)

not specified (1)

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

Computational scores

Splicing

Publications

Other links and lift over