Genetic Variant SH2D3A:p.Gln520Arg (chr19-6753467-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005490.3(SH2D3A):c.1559A>G(p.Gln520Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q520P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SH2D3A
NM_005490.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.46

Publications

0 publications found

Variant links:

Genes affected

SH2D3A (HGNC:16885): (SH2 domain containing 3A) Predicted to enable guanyl-nucleotide exchange factor activity and phosphotyrosine residue binding activity. Predicted to be involved in positive regulation of peptidyl-serine phosphorylation. [provided by Alliance of Genome Resources, Apr 2022]

SH2D3A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.022990465).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005490.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH2D3A	NM_005490.3	MANE Select	c.1559A>G	p.Gln520Arg	missense	Exon 9 of 10	NP_005481.2	Q9BRG2-1
SH2D3A	NM_001439225.1		c.1646A>G	p.Gln549Arg	missense	Exon 8 of 9	NP_001426154.1
SH2D3A	NM_001386585.1		c.1556A>G	p.Gln519Arg	missense	Exon 9 of 10	NP_001373514.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH2D3A	ENST00000245908.11	TSL:1 MANE Select	c.1559A>G	p.Gln520Arg	missense	Exon 9 of 10	ENSP00000245908.5	Q9BRG2-1
SH2D3A	ENST00000892014.1		c.1646A>G	p.Gln549Arg	missense	Exon 8 of 9	ENSP00000562073.1
SH2D3A	ENST00000892016.1		c.1643A>G	p.Gln548Arg	missense	Exon 8 of 9	ENSP00000562075.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1361792

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

667200

African (AFR)

AF:

0.00

AC:

AN:

30698

American (AMR)

AF:

0.00

AC:

AN:

31682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23242

East Asian (EAS)

AF:

0.00

AC:

AN:

34814

South Asian (SAS)

AF:

0.00

AC:

AN:

75822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5540

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1056920

Other (OTH)

AF:

0.00

AC:

AN:

56146

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.75

CADD

Benign

8.4

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.0030

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.53

M_CAP

Benign

0.0047

MetaRNN

Benign

0.023

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

PhyloP100

-1.5

PrimateAI

Benign

0.32

PROVEAN

Benign

0.090

REVEL

Benign

0.016

Sift

Benign

0.71

Sift4G

Benign

0.80

Polyphen

0.0

Vest4

0.055

MutPred

0.36

Gain of methylation at Q520 (P = 0.021)

MVP

0.27

MPC

1.4

ClinPred

0.035

GERP RS

-2.2

Varity_R

0.042

gMVP

0.10

Mutation Taster

=98/2

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over