X-124346690-C-T

Position:

chrX-124346690-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_002351.5(SH2D1A):c.48C>T(p.Gly16Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,210,010 control chromosomes in the GnomAD database, including 3 homozygotes. There are 1,222 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., 51 hem., cov: 23)

Exomes 𝑓: 0.0033 ( 3 hom. 1171 hem. )

Consequence

SH2D1A
NM_002351.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0130

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:):

STAG2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant X-124346690-C-T is Benign according to our data. Variant chrX-124346690-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 367872.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-124346690-C-T is described in Lovd as [Likely_benign]. Variant chrX-124346690-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.013 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 51 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH2D1A	NM_002351.5 linkuse as main transcript	c.48C>T	p.Gly16Gly	synonymous_variant	1/4	ENST00000371139.9	NP_002342.1	O60880-1
SH2D1A	NM_001114937.3 linkuse as main transcript	c.48C>T	p.Gly16Gly	synonymous_variant	1/4		NP_001108409.1	O60880-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH2D1A	ENST00000371139.9 linkuse as main transcript	c.48C>T	p.Gly16Gly	synonymous_variant	1/4	1	NM_002351.5	ENSP00000360181.5		O60880-1

Frequencies

GnomAD3 genomes

AF:

0.00193

AC:

217

AN:

112345

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

AN XY:

34529

show subpopulations

Gnomad AFR

AF:

0.000356

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00112

Gnomad ASJ

AF:

0.000377

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000163

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00355

Gnomad OTH

AF:

0.00199

GnomAD3 exomes

AF:

0.00198

AC:

363

AN:

183390

Hom.:

AF XY:

0.00201

AC XY:

136

AN XY:

67830

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00124

Gnomad ASJ exome

AF:

0.00120

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.000628

Gnomad NFE exome

AF:

0.00366

Gnomad OTH exome

AF:

0.00154

GnomAD4 exome

AF:

0.00327

AC:

3592

AN:

1097613

Hom.:

Cov.:

AF XY:

0.00323

AC XY:

1171

AN XY:

362979

show subpopulations

Gnomad4 AFR exome

AF:

0.000530

Gnomad4 AMR exome

AF:

0.00131

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.000519

Gnomad4 NFE exome

AF:

0.00399

Gnomad4 OTH exome

AF:

0.00265

GnomAD4 genome

AF:

0.00193

AC:

217

AN:

112397

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

AN XY:

34591

show subpopulations

Gnomad4 AFR

AF:

0.000355

Gnomad4 AMR

AF:

0.00112

Gnomad4 ASJ

AF:

0.000377

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000163

Gnomad4 NFE

AF:

0.00355

Gnomad4 OTH

AF:

0.00197

Alfa

AF:

0.000801

Hom.:

Bravo

AF:

0.00203

EpiCase

AF:

0.00273

EpiControl

AF:

0.00415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2017	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 16, 2021	This variant is associated with the following publications: (PMID: 9771704, 24616127) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

X-linked lymphoproliferative disease due to SH2D1A deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Mullegama-Klein-Martinez syndrome;C5393308:Holoprosencephaly 13, X-linked

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

7.9

DANN

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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