12-111447546-TATGGG-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_005475.3(SH2B3):c.1236+3_1236+7del variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.0000846 in 650,192 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000084 (0 hom.)
• Consequence: SH2B3 NM_005475.3 splice_donor_5th_base, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.78

Genes affected

SH2B3 (HGNC:29605): (SH2B adaptor protein 3) This gene encodes a member of the SH2B adaptor family of proteins, which are involved in a range of signaling activities by growth factor and cytokine receptors. The encoded protein is a key negative regulator of cytokine signaling and plays a critical role in hematopoiesis. Mutations in this gene have been associated with susceptibility to celiac disease type 13 and susceptibility to insulin-dependent diabetes mellitus. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

ATXN2 (HGNC:10555): (ataxin 2) This gene belongs to a group of genes that is associated with microsatellite-expansion diseases, a class of neurological and neuromuscular disorders caused by expansion of short stretches of repetitive DNA. The protein encoded by this gene has two globular domains near the N-terminus, one of which contains a clathrin-mediated trans-Golgi signal and an endoplasmic reticulum exit signal. The encoded cytoplasmic protein localizes to the endoplasmic reticulum and plasma membrane, is involved in endocytosis, and modulates mTOR signals, modifying ribosomal translation and mitochondrial function. The N-terminal region of the protein contains a polyglutamine tract of 14-31 residues that can be expanded in the pathogenic state to 32-200 residues. Intermediate length expansions of this tract increase susceptibility to amyotrophic lateral sclerosis, while long expansions of this tract result in spinocerebellar ataxia-2, an autosomal-dominantly inherited, neurodegenerative disorder. Genome-wide association studies indicate that loss-of-function mutations in this gene may be associated with susceptibility to type I diabetes, obesity and hypertension. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 12-111447546-TATGGG-T is Benign according to our data. Variant chr12-111447546-TATGGG-T is described in ClinVar as [Likely_benign]. Clinvar id is 3054073.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B3	NM_005475.3	c.1236+3_1236+7del		splice_donor_5th_base_variant, intron_variant		ENST00000341259.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2B3	ENST00000341259.7	c.1236+3_1236+7del		splice_donor_5th_base_variant, intron_variant		1	NM_005475.3	P1
SH2B3	ENST00000538307.1	c.630+3_630+7del		splice_donor_5th_base_variant, intron_variant		2
ATXN2	ENST00000642389.2	c.*171-3364_*171-3360del		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000889 AC: 7 AN: 78696 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00682

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000207

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000874 AC: 18 AN: 206038 Hom.: 0 AF XY: 0.0000699 AC XY: 8 AN XY: 114478

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00133

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000840 AC: 48 AN: 571496 Hom.: 0 AF XY: 0.0000881 AC XY: 26 AN XY: 295004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000329

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00264

Gnomad4 SAS exome AF: 0.0000163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000130

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome AF: 0.0000889 AC: 7 AN: 78696 Hom.: 0 Cov.: 0 AF XY: 0.0000837 AC XY: 3 AN XY: 35828

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00682

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000207

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000169 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SH2B3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs779556283; hg19: chr12-111885350;