12-111447547-ATGGGGTGGGGTGGGG-ATGGGGTGGGGTGGGGTGGGG

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate 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: Likely benign criteria provided, single submitter B:3
• 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

Verdict is Benign. Variant got -10 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_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 621 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.
• 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: 0.00 AC: 181 AN: 89444 Hom.: 2 Cov.: 0 FAILED QC

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

GnomAD3 exomes AF: 0.000617 AC: 114 AN: 184788 Hom.: 1 AF XY: 0.000598 AC XY: 62 AN XY: 103636

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 SAS exome AF: 0.000248

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

Gnomad4 AFR exome AF: 0.000205

Gnomad4 AMR exome AF: 0.000344

Gnomad4 ASJ exome AF: 0.00869

Gnomad4 EAS exome AF: 0.0000282

Gnomad4 SAS exome AF: 0.000206

Gnomad4 FIN exome AF: 0.000246

Gnomad4 NFE exome AF: 0.00345

Gnomad4 OTH exome AF: 0.00190

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

Gnomad4 AFR AF: 0.000451

Gnomad4 AMR AF: 0.000481

Gnomad4 ASJ AF: 0.00871

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00183

Gnomad4 FIN AF: 0.000887

Gnomad4 NFE AF: 0.00384

Gnomad4 OTH AF: 0.000816

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

- -

not specified Benign:1

Jul 30, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs111340708; hg19: chr12-111885351;