12-111447547-A-ATGGGG

Variant names:

• chr12-111447547-A-ATGGGG
• rs111340708
• NM_005475.3:c.1236+24_1236+28dupTGGGG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000341259.7(SH2B3):​c.1236+3_1236+4insTGGGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 0)
  • Exomes 𝑓: 0.0024 (4 hom.)
  • Failed GnomAD Quality Control
• Consequence: SH2B3 ENST00000341259.7 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.80

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

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-111447547-A-ATGGGG is Benign according to our data. Variant chr12-111447547-A-ATGGGG is described in ClinVar as [Likely_benign]. Clinvar id is 1285139.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00239 (1189/498274) while in subpopulation NFE AF = 0.00345 (1033/299050). AF 95% confidence interval is 0.00328. There are 4 homozygotes in GnomAdExome4. There are 621 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3	c.1236+24_1236+28dupTGGGG		intron_variant	Intron 6 of 7	ENST00000341259.7	NP_005466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B3	ENST00000341259.7	c.1236+3_1236+4insTGGGG		splice_region_variant, intron_variant	Intron 6 of 7	1	NM_005475.3	ENSP00000345492.2
SH2B3	ENST00000538307.1	c.630+3_630+4insTGGGG		splice_region_variant, intron_variant	Intron 5 of 6	2		ENSP00000440597.1
ATXN2	ENST00000642389.2	n.*171-3361_*171-3360insCCCCA		intron_variant	Intron 26 of 26			ENSP00000496055.2

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 181 AN: 89444 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.000453

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000482

Gnomad ASJ AF: 0.00871

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00184

Gnomad FIN AF: 0.000887

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.000825

GnomAD2 exomes AF: 0.000617 AC: 114 AN: 184788 AF XY: 0.000598

Gnomad AFR exome AF: 0.000159

Gnomad AMR exome AF: 0.000394

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000624

Gnomad FIN exome AF: 0.000121

Gnomad NFE exome AF: 0.000962

Gnomad OTH exome AF: 0.000254

GnomAD4 exome AF: 0.00239 AC: 1189 AN: 498274 Hom.: 4 Cov.: 0 AF XY: 0.00238 AC XY: 621 AN XY: 261136

African (AFR) AF: 0.000205 AC: 4 AN: 19554

American (AMR) AF: 0.000344 AC: 9 AN: 26138

Ashkenazi Jewish (ASJ) AF: 0.00869 AC: 79 AN: 9092

East Asian (EAS) AF: 0.0000282 AC: 1 AN: 35510

South Asian (SAS) AF: 0.000206 AC: 11 AN: 53316

European-Finnish (FIN) AF: 0.000246 AC: 7 AN: 28470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3422

European-Non Finnish (NFE) AF: 0.00345 AC: 1033 AN: 299050

Other (OTH) AF: 0.00190 AC: 45 AN: 23722

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00202 AC: 181 AN: 89568 Hom.: 2 Cov.: 0 AF XY: 0.00186 AC XY: 79 AN XY: 42494

African (AFR) AF: 0.000451 AC: 14 AN: 31010

American (AMR) AF: 0.000481 AC: 4 AN: 8322

Ashkenazi Jewish (ASJ) AF: 0.00871 AC: 14 AN: 1608

East Asian (EAS) AF: 0.00 AC: 0 AN: 4266

South Asian (SAS) AF: 0.00183 AC: 5 AN: 2726

European-Finnish (FIN) AF: 0.000887 AC: 3 AN: 3384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 184

European-Non Finnish (NFE) AF: 0.00384 AC: 140 AN: 36434

Other (OTH) AF: 0.000816 AC: 1 AN: 1226

Alfa AF: 0.000406 Hom.: 272

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Jul 30, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs111340708; hg19: chr12-111885351;