16-28866174-G-A

Variant names:

• chr16-28866174-G-A
• rs559282918
• NM_001387430.1:c.80G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001387430.1(SH2B1):​c.80G>A​(p.Arg27Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000089 in 1,561,372 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (1 hom.)
• Consequence: SH2B1 NM_001387430.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.12

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023930252).
• BS2: High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SH2B1	NM_001387430.1	c.80G>A	p.Arg27Gln	missense_variant	Exon 1 of 8	ENST00000684370.1	NP_001374359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SH2B1	ENST00000684370.1	c.80G>A	p.Arg27Gln	missense_variant	Exon 1 of 8		NM_001387430.1	ENSP00000507475.1

Frequencies

GnomAD3 genomes AF: 0.0000660 AC: 10 AN: 151522 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000162 AC: 27 AN: 166494 Hom.: 0 AF XY: 0.000197 AC XY: 18 AN XY: 91582

Gnomad AFR exome AF: 0.000120

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000798

Gnomad SAS exome AF: 0.000861

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000447

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.0000915 AC: 129 AN: 1409736 Hom.: 1 Cov.: 37 AF XY: 0.000123 AC XY: 86 AN XY: 697282

Gnomad4 AFR exome AF: 0.0000312

Gnomad4 AMR exome AF: 0.0000265

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000272

Gnomad4 SAS exome AF: 0.000915

Gnomad4 FIN exome AF: 0.000108

Gnomad4 NFE exome AF: 0.0000395

Gnomad4 OTH exome AF: 0.0000686

GnomAD4 genome AF: 0.0000659 AC: 10 AN: 151636 Hom.: 0 Cov.: 32 AF XY: 0.0000945 AC XY: 7 AN XY: 74076

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000417

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000737

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000589 Hom.: 0

ExAC AF: 0.000137 AC: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.80G>A (p.R27Q) alteration is located in exon 2 (coding exon 1) of the SH2B1 gene. This alteration results from a G to A substitution at nucleotide position 80, causing the arginine (R) at amino acid position 27 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SH2B1-related disorder Uncertain:1

Dec 06, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SH2B1 c.80G>A variant is predicted to result in the amino acid substitution p.Arg27Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.086% of alleles in individuals of South Asian descent in gnomAD, which may be too common to be an unreported cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;T;.;T;T;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;.;.;D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.024	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;L;L;.;L;L;L
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-2.6	D;N;N;N;.;N;N
REVEL	Benign	0.038
Sift	Benign	0.46	T;T;T;T;.;T;T
Sift4G	Benign	0.51	T;T;T;T;T;T;T
Polyphen		0.0080, 0.0020	.;B;B;.;B;B;B
Vest4		0.23, 0.14, 0.23, 0.22
MVP		0.26
MPC		0.28
ClinPred		0.038	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.063
gMVP		0.25

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: rs559282918; hg19: chr16-28877495;