16-28866167-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001387430.1(SH2B1):c.73A>T(p.Ser25Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SH2B1 NM_001387430.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47

Genes affected

SH2B1 (HGNC:30417): (SH2B adaptor protein 1) This gene encodes a member of the SH2-domain containing mediators family. The encoded protein mediates activation of various kinases and may function in cytokine and growth factor receptor signaling and cellular transformation. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3188706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SH2B1	NM_001387430.1	c.73A>T	p.Ser25Cys	missense_variant	1/8	ENST00000684370.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SH2B1	ENST00000684370.1	c.73A>T	p.Ser25Cys	missense_variant	1/8		NM_001387430.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000871 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2023

The c.73A>T (p.S25C) alteration is located in exon 2 (coding exon 1) of the SH2B1 gene. This alteration results from a A to T substitution at nucleotide position 73, causing the serine (S) at amino acid position 25 to be replaced by a cysteine (C). 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	0.21
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Benign	0.096	T;T;.;T;T;.;.
Eigen	Benign	-0.0022
Eigen_PC	Benign	-0.00083
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.76	T;.;.;T;T;T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.4	N;N;N;N;.;N;N
Sift	Uncertain	0.014	D;D;D;D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.85, 0.64	.;P;P;.;P;P;P
Vest4		0.59, 0.42, 0.59, 0.65, 0.60
MutPred		0.49		Gain of catalytic residue at W26 (P = 7e-04);Gain of catalytic residue at W26 (P = 7e-04);Gain of catalytic residue at W26 (P = 7e-04);Gain of catalytic residue at W26 (P = 7e-04);Gain of catalytic residue at W26 (P = 7e-04);Gain of catalytic residue at W26 (P = 7e-04);Gain of catalytic residue at W26 (P = 7e-04);
MVP		0.10
MPC		0.85
ClinPred		0.65	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.52

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: rs756872302; hg19: chr16-28877488;