X-124346695-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6

The NM_002351.5(SH2D1A):c.53A>G(p.Lys18Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,210,301 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000021 ( 0 hom. 8 hem. )

Consequence

SH2D1A
NM_002351.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 1.26

Variant links:

Genes affected

SH2D1A (HGNC:10820): (SH2 domain containing 1A) This gene encodes a protein that plays a major role in the bidirectional stimulation of T and B cells. This protein contains an SH2 domain and a short tail. It associates with the signaling lymphocyte-activation molecule, thereby acting as an inhibitor of this transmembrane protein by blocking the recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to its docking site. This protein can also bind to other related surface molecules that are expressed on activated T, B and NK cells, thereby modifying signal transduction pathways in these cells. Mutations in this gene cause lymphoproliferative syndrome X-linked type 1 or Duncan disease, a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus, with symptoms including severe mononucleosis and malignant lymphoma. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

SH2D1A links:

STAG2 (HGNC:11355): (STAG2 cohesin complex component) The protein encoded by this gene is a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Targeted inactivation of this gene results in chromatid cohesion defects and aneuploidy, suggesting that genetic disruption of cohesin is a cause of aneuploidy in human cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2013]

STAG2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a domain SH2 (size 98) in uniprot entity SH21A_HUMAN there are 23 pathogenic changes around while only 2 benign (92%) in NM_002351.5

BP4

Computational evidence support a benign effect (MetaRNN=0.16648412).

BP6

Variant X-124346695-A-G is Benign according to our data. Variant chrX-124346695-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 450974.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2D1A	NM_002351.5 linkuse as main transcript	c.53A>G	p.Lys18Arg	missense_variant	1/4	ENST00000371139.9
SH2D1A	NM_001114937.3 linkuse as main transcript	c.53A>G	p.Lys18Arg	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2D1A	ENST00000371139.9 linkuse as main transcript	c.53A>G	p.Lys18Arg	missense_variant	1/4	1	NM_002351.5	P3	O60880-1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112406

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34586

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183424

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000209

AC:

AN:

1097895

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

363257

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000273

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112406

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34586

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 11, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	- -

X-linked lymphoproliferative disease due to SH2D1A deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 08, 2023

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 18 of the SH2D1A protein (p.Lys18Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with SH2D1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 450974). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Uncertain

0.51

D;.;.

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

-0.050

N;N;N

MutationTaster

Benign

0.84

D;D

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.63

N;N;.

REVEL

Benign

0.20

Sift

Benign

0.41

T;T;.

Sift4G

Benign

0.53

T;T;T

Polyphen

0.0070

B;B;.

Vest4

0.16

MVP

0.88

MPC

0.99

ClinPred

0.17

GERP RS

1.9

Varity_R

0.12

gMVP

0.77

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