Variant chr12-111406282-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP3_ModerateBP6

The NM_005475.3(SH2B3):c.-28+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 152,302 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.016 ( 0 hom. )

Consequence

SH2B3
NM_005475.3 splice_donor_5th_base, intron

Scores

Splicing: ADA: 0.9997

Clinical Significance

Likely benign no assertion criteria provided B:2

Conservation

PhyloP100: 2.59

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]

SH2B3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 12-111406282-G-A is Benign according to our data. Variant chr12-111406282-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1299799.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B3	NM_005475.3 linkuse as main transcript	c.-28+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000341259.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2B3	ENST00000341259.7 linkuse as main transcript	c.-28+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_005475.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00287

AC:

436

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0106

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00412

Gnomad OTH

AF:

0.00239

GnomAD4 exome

AF:

0.0156

AC:

AN:

Hom.:

Cov.:

AF XY:

0.0200

AC XY:

AN XY:

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0200

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00286

AC:

436

AN:

152238

Hom.:

Cov.:

AF XY:

0.00284

AC XY:

211

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000529

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.0106

Gnomad4 NFE

AF:

0.00412

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00218

Hom.:

Bravo

AF:

0.00207

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

0.090

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over