dbSNP rs779622961: SH2B3:p.Ser16* (chr12-111418192-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_005475.3(SH2B3):c.47C>A(p.Ser16*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SH2B3
NM_005475.3 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.374

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

syndromic disease
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
acute lymphoblastic leukemia
Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
growth retardation-mild developmental delay-chronic hepatitis syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
primary familial polycythemia due to EPO receptor mutation
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
schizophrenia
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)
thrombocythemia 1
Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

SH2B3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B3	NM_005475.3	MANE Select	c.47C>A	p.Ser16*	stop_gained	Exon 2 of 8	NP_005466.1	Q9UQQ2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SH2B3	ENST00000341259.7	TSL:1 MANE Select	c.47C>A	p.Ser16*	stop_gained	Exon 2 of 8	ENSP00000345492.2	Q9UQQ2
SH2B3	ENST00000896496.1		c.47C>A	p.Ser16*	stop_gained	Exon 2 of 8	ENSP00000566555.1
SH2B3	ENST00000935782.1		c.47C>A	p.Ser16*	stop_gained	Exon 2 of 8	ENSP00000605841.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000495

AC:

AN:

201940

AF XY:

0.00000885

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1419470

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705986

African (AFR)

AF:

0.00

AC:

AN:

30854

American (AMR)

AF:

0.00

AC:

AN:

40454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24634

East Asian (EAS)

AF:

0.00

AC:

AN:

38312

South Asian (SAS)

AF:

0.00

AC:

AN:

81924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37904

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4214

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102114

Other (OTH)

AF:

0.00

AC:

AN:

59060

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000859

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Benign

0.96

Eigen

Benign

0.0094

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.21

PhyloP100

0.37

Vest4

0.27

GERP RS

1.3

PromoterAI

0.015

Neutral

(source)

Mutation Taster

=26/174

disease causing (fs/PTC)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over