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12-111444796-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

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

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0430
Variant links:
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]

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ACMG classification

Classification made for transcript

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 GnomAd at 4 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SH2B3NM_005475.3 linkuse as main transcriptc.733-1957G>A intron_variant ENST00000341259.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SH2B3ENST00000341259.7 linkuse as main transcriptc.733-1957G>A intron_variant 1 NM_005475.3 P1
SH2B3ENST00000550925.2 linkuse as main transcriptc.598G>A p.Ala200Thr missense_variant 2/25
SH2B3ENST00000538307.1 linkuse as main transcriptc.127-1957G>A intron_variant 2
ATXN2ENST00000642389.2 linkuse as main transcriptc.*171-609C>T intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.00912
AC:
1389
AN:
152232
Hom.:
4
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2023SH2B3: 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs112564165; hg19: chr12-111882600; API