dbSNP rs759758469: SH2B3:p.Asn2Lys (chr12-111418151-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005475.3(SH2B3):c.6C>G(p.Asn2Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000443 in 1,355,704 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N2N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

SH2B3
NM_005475.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.440

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):

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B3	NM_005475.3 link	c.6C>G	p.Asn2Lys	missense_variant	Exon 2 of 8	ENST00000341259.7	NP_005466.1	Q9UQQ2Q59H48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B3	ENST00000341259.7 link	c.6C>G	p.Asn2Lys	missense_variant	Exon 2 of 8	1	NM_005475.3	ENSP00000345492.2		Q9UQQ2
SH2B3	ENST00000550925.2 link	c.-190C>G		upstream_gene_variant		5		ENSP00000473529.1		R4GN84

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

150976

AF XY:

0.0000237

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000999

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:

0.000286

GnomAD4 exome

AF:

0.00000443

AC:

AN:

1355704

Hom.:

Cov.:

AF XY:

0.00000747

AC XY:

AN XY:

669234

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27912

American (AMR)

AF:

0.000134

AC:

AN:

29936

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20694

East Asian (EAS)

AF:

0.00

AC:

AN:

35526

South Asian (SAS)

AF:

0.00

AC:

AN:

71404

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35776

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3842

European-Non Finnish (NFE)

AF:

9.31e-7

AC:

AN:

1074254

Other (OTH)

AF:

0.0000177

AC:

AN:

56360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000169

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.48

CADD

Benign

3.5

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.73

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.39

M_CAP

Benign

0.062

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.4

PhyloP100

-0.44

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.11

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0080

Polyphen

0.95

Vest4

0.51

MutPred

0.25

Gain of ubiquitination at N2 (P = 0.0029);

MVP

0.69

MPC

0.86

ClinPred

0.55

GERP RS

-0.47

PromoterAI

-0.055

Neutral

(source)

Varity_R

0.28

gMVP

0.59

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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rs759758469

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over