12-111418639-C-G

Position:

• chr12-111418639-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005475.3(SH2B3):​c.494C>G​(p.Thr165Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.019 in 1,475,164 control chromosomes in the GnomAD database, including 4,488 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (2670 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (1818 hom.)
• Consequence: SH2B3 NM_005475.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.570

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003297031).
• BP6: Variant 12-111418639-C-G is Benign according to our data. Variant chr12-111418639-C-G is described in ClinVar as [Benign]. Clinvar id is 380743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B3	NM_005475.3	c.494C>G	p.Thr165Ser	missense_variant	2/8	ENST00000341259.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2B3	ENST00000341259.7	c.494C>G	p.Thr165Ser	missense_variant	2/8	1	NM_005475.3	P1
SH2B3	ENST00000550925.2	c.302C>G	p.Thr101Ser	missense_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15496 AN: 151778 Hom.: 2651 Cov.: 32

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0415

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.0648

GnomAD3 exomes AF: 0.0136 AC: 1309 AN: 96240 Hom.: 152 AF XY: 0.0112 AC XY: 622 AN XY: 55378

Gnomad AFR exome AF: 0.331

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.00213

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00263

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00973

GnomAD4 exome AF: 0.00947 AC: 12533 AN: 1323278 Hom.: 1818 Cov.: 32 AF XY: 0.00850 AC XY: 5561 AN XY: 654080

Gnomad4 AFR exome AF: 0.361

Gnomad4 AMR exome AF: 0.0201

Gnomad4 ASJ exome AF: 0.00338

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00301

Gnomad4 FIN exome AF: 0.0000598

Gnomad4 NFE exome AF: 0.000898

Gnomad4 OTH exome AF: 0.0228

GnomAD4 genome AF: 0.102 AC: 15559 AN: 151886 Hom.: 2670 Cov.: 32 AF XY: 0.0984 AC XY: 7309 AN XY: 74252

Gnomad4 AFR AF: 0.353

Gnomad4 AMR AF: 0.0414

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.0642

Alfa AF: 0.0196 Hom.: 44

Bravo AF: 0.116

ESP6500AA AF: 0.163 AC: 323

ESP6500EA AF: 0.00151 AC: 8

ExAC AF: 0.0169 AC: 1762

Asia WGS AF: 0.0190 AC: 63 AN: 3364

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 09, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 31, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

SH2B3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.28
DANN	Benign	0.43
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.053
Sift	Benign	0.72	T
Sift4G	Benign	0.79	T
Polyphen		0.0030	B
Vest4		0.026
MutPred		0.17		Loss of catalytic residue at T165 (P = 0.0526);
MPC		0.67
ClinPred		0.0019	T
GERP RS		0.69
Varity_R		0.031
gMVP		0.14

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

Other links and lift over

dbSNP: rs7963692; hg19: chr12-111856443;