rs111340708

Variant names:

• chr12-111447547-ATGGGGTGGGGTGGGG-A
• rs111340708
• NM_005475.3:c.1236+14_1236+28delTGGGGTGGGGTGGGG

Your query was ambiguous. Multiple possible variants found:

• chr12-111447547-ATGGGGTGGGGTGGGG-A
• chr12-111447547-ATGGGGTGGGGTGGGG-ATGGGG
• chr12-111447547-ATGGGGTGGGGTGGGG-ATGGGGTGGGG
• chr12-111447547-ATGGGGTGGGGTGGGG-ATGGGGTGGGGTGGGGTGGGG
• chr12-111447547-ATGGGGTGGGGTGGGG-ATGGGGTGGGGTGGGGTGGGGTGGGG
• chr12-111447547-ATGGGGTGGGGTGGGG-ATGGGGTGGGGTGGGGTGGGGTGGGGTGGGG

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The ENST00000341259.7(SH2B3):​c.1236+4_1236+18delTGGGGTGGGGTGGGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000221 in 587,712 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000020 (1 hom.)
• Consequence: SH2B3 ENST00000341259.7 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.00

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3	c.1236+14_1236+28delTGGGGTGGGGTGGGG		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+4_1236+18delTGGGGTGGGGTGGGG		splice_region_variant, intron_variant	Intron 6 of 7	1	NM_005475.3	ENSP00000345492.2
SH2B3	ENST00000538307.1	c.630+4_630+18delTGGGGTGGGGTGGGG		splice_region_variant, intron_variant	Intron 5 of 6	2		ENSP00000440597.1
ATXN2	ENST00000642389.2	n.*171-3375_*171-3361delCCCCACCCCACCCCA		intron_variant	Intron 26 of 26			ENSP00000496055.2

Frequencies

GnomAD3 genomes AF: 0.0000335 AC: 3 AN: 89446 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: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000823

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000162 AC: 3 AN: 184788 AF XY: 0.00000965

Gnomad AFR exome AF: 0.0000794

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000235

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000201 AC: 10 AN: 498266 Hom.: 1 AF XY: 0.0000191 AC XY: 5 AN XY: 261132

African (AFR) AF: 0.0000511 AC: 1 AN: 19554

American (AMR) AF: 0.00 AC: 0 AN: 26140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9094

East Asian (EAS) AF: 0.00 AC: 0 AN: 35508

South Asian (SAS) AF: 0.00 AC: 0 AN: 53320

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28470

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

European-Non Finnish (NFE) AF: 0.0000201 AC: 6 AN: 299036

Other (OTH) AF: 0.000126 AC: 3 AN: 23722

GnomAD4 genome AF: 0.0000335 AC: 3 AN: 89446 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 42374

African (AFR) AF: 0.00 AC: 0 AN: 30892

American (AMR) AF: 0.00 AC: 0 AN: 8304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1608

East Asian (EAS) AF: 0.00 AC: 0 AN: 4278

South Asian (SAS) AF: 0.00 AC: 0 AN: 2724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 200

European-Non Finnish (NFE) AF: 0.0000823 AC: 3 AN: 36436

Other (OTH) AF: 0.00 AC: 0 AN: 1212

Alfa AF: 0.00 Hom.: 272

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0

Splicing

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

Publications

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Other links and lift over

dbSNP: rs111340708; hg19: chr12-111885351;