12-111418689-T-C

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.544T>C(p.Phe182Leu) 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 1,489,174 control chromosomes in the GnomAD database, including 4,489 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.10 (2667 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (1822 hom.)
• Consequence: SH2B3 NM_005475.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.852

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=0.0029709637).
• BP6: Variant 12-111418689-T-C is Benign according to our data. Variant chr12-111418689-T-C is described in ClinVar as [Benign]. Clinvar id is 1250441.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B3	NM_005475.3	c.544T>C	p.Phe182Leu	missense_variant	2/8	ENST00000341259.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2B3	ENST00000341259.7	c.544T>C	p.Phe182Leu	missense_variant	2/8	1	NM_005475.3	P1
SH2B3	ENST00000550925.2	c.352T>C	p.Phe118Leu	missense_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15497 AN: 151744 Hom.: 2648 Cov.: 32

Gnomad AFR AF: 0.353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0416

Gnomad ASJ AF: 0.00318

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.0657

GnomAD3 exomes AF: 0.00936 AC: 894 AN: 95508 Hom.: 78 AF XY: 0.00795 AC XY: 435 AN XY: 54734

Gnomad AFR exome AF: 0.309

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.00214

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00319

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00106

Gnomad OTH exome AF: 0.00985

GnomAD4 exome AF: 0.00954 AC: 12760 AN: 1337322 Hom.: 1822 Cov.: 32 AF XY: 0.00855 AC XY: 5649 AN XY: 661004

Gnomad4 AFR exome AF: 0.359

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00337

Gnomad4 FIN exome AF: 0.0000592

Gnomad4 NFE exome AF: 0.000906

Gnomad4 OTH exome AF: 0.0234

GnomAD4 genome AF: 0.102 AC: 15561 AN: 151852 Hom.: 2667 Cov.: 32 AF XY: 0.0985 AC XY: 7310 AN XY: 74246

Gnomad4 AFR AF: 0.353

Gnomad4 AMR AF: 0.0414

Gnomad4 ASJ AF: 0.00318

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.0655

Alfa AF: 0.00633 Hom.: 18

Bravo AF: 0.116

ESP6500AA AF: 0.167 AC: 424

ESP6500EA AF: 0.00178 AC: 11

ExAC AF: 0.0109 AC: 1077

Asia WGS AF: 0.0190 AC: 66 AN: 3424

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	clinical testing	GeneDx	Jan 10, 2019	- -

SH2B3-related disorder Benign:1

Benign, criteria provided, single submitter

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	0.20
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	16
Dann	Benign	0.42
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.8	N
MutationTaster	Benign	1.0	P
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	0.88	N
REVEL	Benign	0.061
Sift	Benign	1.0	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.0080
MutPred		0.077		Loss of solvent accessibility (P = 0.0219);
MPC		0.87
ClinPred		0.0057	T
GERP RS		0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.16

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: rs7972796; hg19: chr12-111856493;