X-124346519-T-C

Variant names:

• chrX-124346519-T-C
• rs148700291
• ENST00000360027.5:c.-124T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000360027.5(SH2D1A):​c.-124T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000147 in 680,811 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000015 (0 hom. 0 hem.)
• Consequence: SH2D1A ENST00000360027.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.361
• Publications: 0 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, G2P, Illumina, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Xq25 microduplication syndrome

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000360027.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D1A	NM_002351.5	MANE Select	c.-124T>C		upstream_gene	N/A	NP_002342.1	O60880-1
	SH2D1A	NM_001114937.3		c.-124T>C		upstream_gene	N/A	NP_001108409.1	O60880-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D1A	ENST00000360027.5	TSL:1	c.-124T>C		5_prime_UTR	Exon 1 of 4	ENSP00000353126.4	O60880-4
	SH2D1A	ENST00000698113.1		c.-124T>C		5_prime_UTR	Exon 2 of 5	ENSP00000513571.1	O60880-1
	SH2D1A	ENST00000698116.1		c.-59+33T>C		intron	N/A	ENSP00000513572.1	O60880-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000147 AC: 1 AN: 680811 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 195465

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 18425

American (AMR) AF: 0.00 AC: 0 AN: 34302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16636

East Asian (EAS) AF: 0.00 AC: 0 AN: 27943

South Asian (SAS) AF: 0.00 AC: 0 AN: 45298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35225

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2414

European-Non Finnish (NFE) AF: 0.00000214 AC: 1 AN: 468266

Other (OTH) AF: 0.00 AC: 0 AN: 32302

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.2
DANN	Benign	0.74
PhyloP100		0.36
PromoterAI		-0.089	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs148700291; hg19: chrX-123480369;