12-111447547-ATGGGG-A

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000341259.7(SH2B3):​c.1236+4_1236+8delTGGGG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 583,428 control chromosomes in the GnomAD database, including 47,682 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (11376 hom., cov: 0)
  • Exomes 𝑓: 0.47 (36306 hom.)
• Consequence: SH2B3 ENST00000341259.7 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 12-111447547-ATGGGG-A is Benign according to our data. Variant chr12-111447547-ATGGGG-A is described in ClinVar as [Benign]. Clinvar id is 1250838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-111447547-ATGGGG-A is described in Lovd as [Benign]. Variant chr12-111447547-ATGGGG-A is described in Lovd as [Likely_benign]. Variant chr12-111447547-ATGGGG-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3	c.1236+24_1236+28delTGGGG		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+8delTGGGG		splice_region_variant, intron_variant	Intron 6 of 7	1	NM_005475.3	ENSP00000345492.2
SH2B3	ENST00000538307.1	c.630+4_630+8delTGGGG		splice_region_variant, intron_variant	Intron 5 of 6	2		ENSP00000440597.1
ATXN2	ENST00000642389.2	n.*171-3365_*171-3361delCCCCA		intron_variant	Intron 26 of 26			ENSP00000496055.2

Frequencies

GnomAD3 genomes AF: 0.531 AC: 47291 AN: 89144 Hom.: 11344 Cov.: 0

Gnomad AFR AF: 0.709

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.518

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.891

Gnomad SAS AF: 0.510

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.565

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.508

GnomAD3 exomes AF: 0.346 AC: 63891 AN: 184788 Hom.: 13013 AF XY: 0.331 AC XY: 34319 AN XY: 103636

Gnomad AFR exome AF: 0.652

Gnomad AMR exome AF: 0.432

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.815

Gnomad SAS exome AF: 0.387

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.227

Gnomad OTH exome AF: 0.322

GnomAD4 exome AF: 0.465 AC: 229884 AN: 494160 Hom.: 36306 AF XY: 0.454 AC XY: 117651 AN XY: 258960

Gnomad4 AFR exome AF: 0.687

Gnomad4 AMR exome AF: 0.450

Gnomad4 ASJ exome AF: 0.268

Gnomad4 EAS exome AF: 0.840

Gnomad4 SAS exome AF: 0.451

Gnomad4 FIN exome AF: 0.298

Gnomad4 NFE exome AF: 0.429

Gnomad4 OTH exome AF: 0.490

GnomAD4 genome AF: 0.531 AC: 47383 AN: 89268 Hom.: 11376 Cov.: 0 AF XY: 0.539 AC XY: 22796 AN XY: 42322

Gnomad4 AFR AF: 0.709

Gnomad4 AMR AF: 0.518

Gnomad4 ASJ AF: 0.242

Gnomad4 EAS AF: 0.890

Gnomad4 SAS AF: 0.509

Gnomad4 FIN AF: 0.461

Gnomad4 NFE AF: 0.364

Gnomad4 OTH AF: 0.505

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 06, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

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

Significance: Benign

Review Status: no assertion criteria provided

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;