12-111447506-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_005475.3(SH2B3):​c.1198G>A​(p.Glu400Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,488,994 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0015 ( 3 hom. )

Consequence

SH2B3
NM_005475.3 missense

Scores

7
6
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.60
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.38761103).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00079 (108/136632) while in subpopulation NFE AF= 0.0014 (90/64434). AF 95% confidence interval is 0.00116. There are 0 homozygotes in gnomad4. There are 47 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SH2B3NM_005475.3 linkc.1198G>A p.Glu400Lys missense_variant Exon 6 of 8 ENST00000341259.7 NP_005466.1 Q9UQQ2Q59H48

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SH2B3ENST00000341259.7 linkc.1198G>A p.Glu400Lys missense_variant Exon 6 of 8 1 NM_005475.3 ENSP00000345492.2 Q9UQQ2
SH2B3ENST00000538307.1 linkc.592G>A p.Glu198Lys missense_variant Exon 5 of 7 2 ENSP00000440597.1 F5GYM4
ATXN2ENST00000642389.2 linkn.*171-3319C>T intron_variant Intron 26 of 26 ENSP00000496055.2 A0A2R8Y7E6

Frequencies

GnomAD3 genomes
AF:
0.000791
AC:
108
AN:
136538
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.000311
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000354
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000150
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00140
Gnomad OTH
AF:
0.000532
GnomAD3 exomes
AF:
0.000582
AC:
144
AN:
247234
Hom.:
0
AF XY:
0.000581
AC XY:
78
AN XY:
134160
show subpopulations
Gnomad AFR exome
AF:
0.000126
Gnomad AMR exome
AF:
0.000203
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000236
Gnomad NFE exome
AF:
0.00113
Gnomad OTH exome
AF:
0.000828
GnomAD4 exome
AF:
0.00151
AC:
2042
AN:
1352362
Hom.:
3
Cov.:
34
AF XY:
0.00148
AC XY:
991
AN XY:
669924
show subpopulations
Gnomad4 AFR exome
AF:
0.000185
Gnomad4 AMR exome
AF:
0.000239
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000283
Gnomad4 NFE exome
AF:
0.00185
Gnomad4 OTH exome
AF:
0.00197
GnomAD4 genome
AF:
0.000790
AC:
108
AN:
136632
Hom.:
0
Cov.:
30
AF XY:
0.000731
AC XY:
47
AN XY:
64306
show subpopulations
Gnomad4 AFR
AF:
0.000310
Gnomad4 AMR
AF:
0.000354
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000150
Gnomad4 NFE
AF:
0.00140
Gnomad4 OTH
AF:
0.000529
Alfa
AF:
0.00110
Hom.:
1
TwinsUK
AF:
0.00324
AC:
12
ALSPAC
AF:
0.00182
AC:
7
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00186
AC:
16
ExAC
AF:
0.000453
AC:
55
EpiCase
AF:
0.000981
EpiControl
AF:
0.00124

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 04, 2024Observed heterozygous in individuals with myelodysplastic syndrome/myeloproliferative neoplasm, juvenile myelomonocytic leukemia, or idiopathic erythrocytosis (PMID: 21990094, 26457647, 27651169, 31173385); Published functional studies demonstrate normal cell growth inhibition (PMID: 21990094); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26607381, 24777453, 27651169, 28484264, 24725463, 31173385, 26457647, 29682367, 33792220, Butler2022[FunctionalStudy], 34662886, 35281324, 35056081, 36324816, 35935937, 38262687, 38417019, 21990094, 33850299, 38862854) -
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 04, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJul 01, 2024PM1 -
Primary myelofibrosis;C3277671:Thrombocythemia 1;C4551637:Primary familial polycythemia due to EPO receptor mutation Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.79
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.87
D;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Benign
0.054
D
MetaRNN
Benign
0.39
T;T
MetaSVM
Benign
-0.57
T
MutationAssessor
Uncertain
2.4
M;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-3.9
D;D
REVEL
Uncertain
0.51
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.010
D;D
Polyphen
1.0
D;D
Vest4
0.67
MVP
0.95
MPC
0.41
ClinPred
0.16
T
GERP RS
5.0
Varity_R
0.77
gMVP
0.49

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: rs72650673; hg19: chr12-111885310; COSMIC: COSV57985448; COSMIC: COSV57985448; API