rs111033630

Variant names:

• chrX-124365787-G-A
• rs111033630
• NM_002351.5:c.164G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-124365787-G-A
• chrX-124365787-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_002351.5(SH2D1A):​c.164G>A​(p.Arg55Gln) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R55L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SH2D1A NM_002351.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.74
• Publications: 8 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 9 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-124365787-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 10910.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant X-124365787-G-A is Pathogenic according to our data. Variant chrX-124365787-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 871639.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2D1A	NM_002351.5	c.164G>A	p.Arg55Gln	missense_variant	Exon 2 of 4	ENST00000371139.9	NP_002342.1
SH2D1A	NM_001114937.3	c.164G>A	p.Arg55Gln	missense_variant	Exon 2 of 4		NP_001108409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2D1A	ENST00000371139.9	c.164G>A	p.Arg55Gln	missense_variant	Exon 2 of 4	1	NM_002351.5	ENSP00000360181.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1063673 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 335141

African (AFR) AF: 0.00 AC: 0 AN: 25786

American (AMR) AF: 0.00 AC: 0 AN: 35156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19146

East Asian (EAS) AF: 0.00 AC: 0 AN: 30017

South Asian (SAS) AF: 0.00 AC: 0 AN: 53308

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40489

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4053

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 810796

Other (OTH) AF: 0.00 AC: 0 AN: 44922

GnomAD4 genome Cov.: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Mar 17, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21119115, 24433830, 32150605, 26878112, Dang2022[CaseReport]) -

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lymphoproliferative disorder Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PM3(strong),PM5,PM2,PP3 -

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

Jun 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 55 of the SH2D1A protein (p.Arg55Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hemophagocytic lymphohistiocytosis and/or X-linked lymphoproliferative syndromes (PMID: 21119115, 32150605). ClinVar contains an entry for this variant (Variation ID: 871639). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Arg55 amino acid residue in SH2D1A. Other variant(s) that disrupt this residue have been observed in individuals with SH2D1A-related conditions (PMID: 11133747), which suggests that this may be a clinically significant amino acid residue. 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	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.28	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.90	D
PhyloP100		6.7
Vest4		0.78
MVP		1.0
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.96
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.14		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: rs111033630; hg19: chrX-123499637; COSMIC: COSV63578771;