X-124346690-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_002351.5(SH2D1A):c.48C>T(p.Gly16=) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G16G) has been classified 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0130

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]

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]

ACMG classification

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 GnomAd at 51 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2D1A	NM_002351.5	c.48C>T	p.Gly16=	synonymous_variant	1/4	ENST00000371139.9
SH2D1A	NM_001114937.3	c.48C>T	p.Gly16=	synonymous_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2D1A	ENST00000371139.9	c.48C>T	p.Gly16=	synonymous_variant	1/4	1	NM_002351.5	P3

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 217 AN: 112345 Hom.: 0 Cov.: 23 AF XY: 0.00148 AC XY: 51 AN XY: 34529

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.: 0 AF XY: 0.00201 AC XY: 136 AN XY: 67830

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.: 3 Cov.: 30 AF XY: 0.00323 AC XY: 1171 AN XY: 362979

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.: 0 Cov.: 23 AF XY: 0.00147 AC XY: 51 AN XY: 34591

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.: 7

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

Submissions by phenotype

not specified Benign:3

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

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) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -

X-linked lymphoproliferative disease due to SH2D1A deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
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. -

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

Other links and lift over

dbSNP: rs72610640; hg19: chrX-123480540; COSMIC: COSV63579295;