12-111418317-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005475.3(SH2B3):c.172C>G(p.Leu58Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SH2B3 NM_005475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.452

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16659287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B3	NM_005475.3	c.172C>G	p.Leu58Val	missense_variant	2/8	ENST00000341259.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2B3	ENST00000341259.7	c.172C>G	p.Leu58Val	missense_variant	2/8	1	NM_005475.3	P1
SH2B3	ENST00000550925.2			upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2022

The c.172C>G (p.L58V) alteration is located in exon 2 (coding exon 1) of the SH2B3 gene. This alteration results from a C to G substitution at nucleotide position 172, causing the leucine (L) at amino acid position 58 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	16
Dann	Benign	0.89
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.97	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.049
Sift	Benign	0.24	T
Sift4G	Benign	0.54	T
Polyphen		0.45	B
Vest4		0.057
MutPred		0.54		Gain of methylation at R59 (P = 0.1188);
MVP		0.50
MPC		0.89
ClinPred		0.24	T
GERP RS		2.1
Varity_R		0.11
gMVP		0.15

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: rs1013284739; hg19: chr12-111856121;