dbSNP rs1969385379: SH2D3A:p.Arg541Leu (chr19-6752702-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005490.3(SH2D3A):c.1622G>T(p.Arg541Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,960 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R541Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SH2D3A
NM_005490.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.27

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13912192).

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.1622G>T	p.Arg541Leu	missense	Exon 10 of 10	NP_005481.2	Q9BRG2-1
SH2D3A	NM_001439225.1		c.1709G>T	p.Arg570Leu	missense	Exon 9 of 9	NP_001426154.1
SH2D3A	NM_001386585.1		c.1619G>T	p.Arg540Leu	missense	Exon 10 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.1622G>T	p.Arg541Leu	missense	Exon 10 of 10	ENSP00000245908.5	Q9BRG2-1
SH2D3A	ENST00000892014.1		c.1709G>T	p.Arg570Leu	missense	Exon 9 of 9	ENSP00000562073.1
SH2D3A	ENST00000892016.1		c.1706G>T	p.Arg569Leu	missense	Exon 9 of 9	ENSP00000562075.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1399960

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690598

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31752

American (AMR)

AF:

0.00

AC:

AN:

35900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25164

East Asian (EAS)

AF:

0.00

AC:

AN:

36024

South Asian (SAS)

AF:

0.00

AC:

AN:

79340

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5672

European-Non Finnish (NFE)

AF:

9.26e-7

AC:

AN:

1079564

Other (OTH)

AF:

0.00

AC:

AN:

58016

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.1

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.0047

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.97

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.69

M_CAP

Benign

0.0064

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.41

PhyloP100

1.3

PrimateAI

Benign

0.36

PROVEAN

Benign

1.9

REVEL

Benign

0.085

Sift

Benign

0.47

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.12

MutPred

0.44

Loss of MoRF binding (P = 0.0186)

MVP

0.45

MPC

1.6

ClinPred

0.043

GERP RS

-3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.046

gMVP

0.35

Mutation Taster

=89/11

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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