rs111033627

Variant names:

• chrX-124370177-C-T
• rs111033627
• NM_002351.5:c.203C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_002351.5(SH2D1A):​c.203C>T​(p.Thr68Ile) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SH2D1A NM_002351.5 missense, splice_region
• Scores: Splicing: ADA: 0.7610
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.24
• Publications: 4 publications found

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]

STAG2 Gene-Disease associations (from GenCC):

• Mullegama-Klein-Martinez syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• Xq25 microduplication syndrome

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a domain SH2 (size 98) in uniprot entity SH21A_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_002351.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D1A	NM_002351.5	c.203C>T	p.Thr68Ile	missense_variant, splice_region_variant	Exon 3 of 4	ENST00000371139.9	NP_002342.1
SH2D1A	NM_001114937.3	c.203C>T	p.Thr68Ile	missense_variant, splice_region_variant	Exon 3 of 4		NP_001108409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2D1A	ENST00000371139.9	c.203C>T	p.Thr68Ile	missense_variant, splice_region_variant	Exon 3 of 4	1	NM_002351.5	ENSP00000360181.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked lymphoproliferative disease due to SH2D1A deficiency Pathogenic:1 Uncertain:1

Sep 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as 502C>T. ClinVar contains an entry for this variant (Variation ID: 10905). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SH2D1A function (PMID: 11414741, 11477068). 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. This missense change has been observed in individuals with X-linked recessive lymphoproliferative syndrome (PMID: 9771704, 11414741). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 68 of the SH2D1A protein (p.Thr68Ile). This variant is not present in population databases (gnomAD no frequency). -

Oct 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		6.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.046	D;D
Polyphen		1.0	D;D
Vest4		0.82
MutPred		0.79		Loss of disorder (P = 0.0185);Loss of disorder (P = 0.0185);
MVP		0.99
MPC		2.5
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.91
gMVP		0.92
Mutation Taster		=45/55	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.76
dbscSNV1_RF	Pathogenic	0.84
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

Other links and lift over

dbSNP: rs111033627; hg19: chrX-123504027;