rs111033623

chrX-124365786-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002351.5(SH2D1A):c.163C>T(p.Arg55Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SH2D1A NM_002351.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.14

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-124365786-C-T is Pathogenic according to our data. Variant chrX-124365786-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 10898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-124365786-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2D1A	NM_002351.5	c.163C>T	p.Arg55Ter	stop_gained	2/4	ENST00000371139.9
SH2D1A	NM_001114937.3	c.163C>T	p.Arg55Ter	stop_gained	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2D1A	ENST00000371139.9	c.163C>T	p.Arg55Ter	stop_gained	2/4	1	NM_002351.5	P3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1063904 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 335730

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 15, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 10898). This variant is also known as C462T. This premature translational stop signal has been observed in individual(s) with X-linked lymphoproliferative disease (PMID: 9771704, 11520777, 19621458, 24923536, 27209435). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg55*) in the SH2D1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SH2D1A are known to be pathogenic (PMID: 9771704, 11049992, 15711562). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 05, 2000	- -

X-linked lymphoproliferative syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 19, 2017

Variant summary: The SH2D1A c.163C>T (p.Arg55X) variant results in a premature termination codon, predicted to cause a truncated or absent SH2D1A protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Functional studies showed no signaling lymphocyte activation moleculeassociated protein (SAP) expression in NK cells and no (or limited) expression in T cells in XLP patients. One truncation downstream of this position has been classified as pathogenic by our laboratory (e.g. c.191G>A, p.Trp64X). One in silico tool predicts a damaging outcome for this variant. The variant of interest was absent in a large, broad control population, ExAC in 0/87863 control chromosomes. This variant was found in multiple patients with XLP (Marsh_SH2S1A_BioBlood&MarrowTranspl_2014, Chen_ItJouPed_2016, Palendira_JEM_2012). Multiple clinical diagnostic laboratories/reputable databases (including OMIM) classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	36
Dann	Uncertain	1.0
FATHMM_MKL	Benign	0.64	D
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: -25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs111033623; hg19: chrX-123499636; COSMIC: COSV63579201;