12-111444796-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005475.3(SH2B3):c.733-1957G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 985,550 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0091 (4 hom., cov: 33)
  • Exomes 𝑓: 0.014 (100 hom.)
• Consequence: SH2B3 NM_005475.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0430

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-111444796-G-A is Benign according to our data. Variant chr12-111444796-G-A is described in ClinVar as [Benign]. Clinvar id is 2570848.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B3	NM_005475.3	c.733-1957G>A		intron_variant		ENST00000341259.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2B3	ENST00000341259.7	c.733-1957G>A		intron_variant		1	NM_005475.3	P1
SH2B3	ENST00000550925.2	c.598G>A	p.Ala200Thr	missense_variant	2/2	5
SH2B3	ENST00000538307.1	c.127-1957G>A		intron_variant		2
ATXN2	ENST00000642389.2	c.*171-609C>T		intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00912 AC: 1389 AN: 152232 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.0172 AC: 1 AN: 58 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 18

Gnomad AFR exome AF: 0.125

Gnomad ASJ 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: 0.0141 AC: 11730 AN: 833200 Hom.: 100 Cov.: 30 AF XY: 0.0143 AC XY: 5514 AN XY: 384800

Gnomad4 AFR exome AF: 0.0110

Gnomad4 AMR exome AF: 0.00203

Gnomad4 ASJ exome AF: 0.00446

Gnomad4 EAS exome AF: 0.000275

Gnomad4 SAS exome AF: 0.00128

Gnomad4 FIN exome AF: 0.00357

Gnomad4 NFE exome AF: 0.0147

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00912 AC: 1390 AN: 152350 Hom.: 4 Cov.: 33 AF XY: 0.00830 AC XY: 618 AN XY: 74498

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.0113 Hom.: 1

Bravo AF: 0.00908

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

SH2B3: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.6
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs112564165; hg19: chr12-111882600;