chrX-124346569-T-A

Variant names:

• chrX-124346569-T-A
• rs142160401
• NM_002351.5:c.-74T>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002351.5(SH2D1A):​c.-74T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000684 in 1,146,915 control chromosomes in the GnomAD database, including 1 homozygotes. There are 277 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., 33 hem., cov: 23)
  • Exomes 𝑓: 0.00069 (1 hom. 244 hem.)
• Consequence: SH2D1A NM_002351.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.114
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-124346569-T-A is Benign according to our data. Variant chrX-124346569-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 367870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 33 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002351.5. 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.-74T>A		5_prime_UTR	Exon 1 of 4	NP_002342.1	O60880-1
	SH2D1A	NM_001114937.3		c.-74T>A		5_prime_UTR	Exon 1 of 4	NP_001108409.1	O60880-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2D1A	ENST00000371139.9	TSL:1 MANE Select	c.-74T>A		5_prime_UTR	Exon 1 of 4	ENSP00000360181.5	O60880-1
	SH2D1A	ENST00000360027.5	TSL:1	c.-74T>A		5_prime_UTR	Exon 1 of 4	ENSP00000353126.4	O60880-4
	SH2D1A	ENST00000698113.1		c.-74T>A		5_prime_UTR	Exon 2 of 5	ENSP00000513571.1	O60880-1

Frequencies

GnomAD3 genomes AF: 0.000675 AC: 76 AN: 112603 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00325

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.000713

Gnomad OTH AF: 0.000660

GnomAD4 exome AF: 0.000686 AC: 709 AN: 1034258 Hom.: 1 Cov.: 20 AF XY: 0.000774 AC XY: 244 AN XY: 315122

African (AFR) AF: 0.000119 AC: 3 AN: 25218

American (AMR) AF: 0.000684 AC: 24 AN: 35091

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18981

East Asian (EAS) AF: 0.00 AC: 0 AN: 29868

South Asian (SAS) AF: 0.00179 AC: 94 AN: 52548

European-Finnish (FIN) AF: 0.0000253 AC: 1 AN: 39583

Middle Eastern (MID) AF: 0.0147 AC: 56 AN: 3800

European-Non Finnish (NFE) AF: 0.000622 AC: 488 AN: 785120

Other (OTH) AF: 0.000976 AC: 43 AN: 44049

GnomAD4 genome AF: 0.000675 AC: 76 AN: 112657 Hom.: 0 Cov.: 23 AF XY: 0.000948 AC XY: 33 AN XY: 34815

African (AFR) AF: 0.000193 AC: 6 AN: 31058

American (AMR) AF: 0.00197 AC: 21 AN: 10685

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00326 AC: 9 AN: 2764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6197

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.000713 AC: 38 AN: 53295

Other (OTH) AF: 0.000652 AC: 1 AN: 1534

Alfa AF: 0.000645 Hom.: 5

Bravo AF: 0.000510

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	X-linked lymphoproliferative disease due to SH2D1A deficiency (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.7
DANN	Benign	0.82
PhyloP100		-0.11
PromoterAI		0.049	Neutral
Mutation Taster		=300/0	polymorphism

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: rs142160401; hg19: chrX-123480419;