rs7498665

Positions:

• chr16-28871920-A-G
• chr16-28871920-A-T

Variant summary

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

The NM_001387430.1(SH2B1):​c.1450A>G​(p.Thr484Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 1,565,774 control chromosomes in the GnomAD database, including 114,338 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 0.35 (9276 hom., cov: 23)
  • Exomes 𝑓: 0.38 (105062 hom.)
• Consequence: SH2B1 NM_001387430.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.432

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.3735247E-4).
• BP6: Variant 16-28871920-A-G is Benign according to our data. Variant chr16-28871920-A-G is described in ClinVar as [Benign]. Clinvar id is 1232867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.4 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SH2B1	NM_001387430.1	c.1450A>G	p.Thr484Ala	missense_variant	5/8	ENST00000684370.1	NP_001374359.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SH2B1	ENST00000684370.1	c.1450A>G	p.Thr484Ala	missense_variant	5/8		NM_001387430.1	ENSP00000507475	P3

Frequencies

GnomAD3 genomes AF: 0.346 AC: 50546 AN: 146026 Hom.: 9247 Cov.: 23

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.408

Gnomad ASJ AF: 0.270

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.395

Gnomad OTH AF: 0.309

GnomAD3 exomes AF: 0.351 AC: 87551 AN: 249400 Hom.: 17007 AF XY: 0.343 AC XY: 46316 AN XY: 134960

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.488

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.102

Gnomad SAS exome AF: 0.229

Gnomad FIN exome AF: 0.425

Gnomad NFE exome AF: 0.388

Gnomad OTH exome AF: 0.347

GnomAD4 exome AF: 0.379 AC: 538478 AN: 1419620 Hom.: 105062 Cov.: 30 AF XY: 0.375 AC XY: 265080 AN XY: 707606

Gnomad4 AFR exome AF: 0.261

Gnomad4 AMR exome AF: 0.493

Gnomad4 ASJ exome AF: 0.278

Gnomad4 EAS exome AF: 0.141

Gnomad4 SAS exome AF: 0.228

Gnomad4 FIN exome AF: 0.436

Gnomad4 NFE exome AF: 0.400

Gnomad4 OTH exome AF: 0.352

GnomAD4 genome AF: 0.346 AC: 50639 AN: 146154 Hom.: 9276 Cov.: 23 AF XY: 0.345 AC XY: 24546 AN XY: 71228

Gnomad4 AFR AF: 0.270

Gnomad4 AMR AF: 0.409

Gnomad4 ASJ AF: 0.270

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.433

Gnomad4 NFE AF: 0.395

Gnomad4 OTH AF: 0.313

Alfa AF: 0.370 Hom.: 5748

Bravo AF: 0.339

TwinsUK AF: 0.396 AC: 1468

ALSPAC AF: 0.401 AC: 1545

ESP6500AA AF: 0.270 AC: 1188

ESP6500EA AF: 0.381 AC: 3280

ExAC AF: 0.345 AC: 41888

Asia WGS AF: 0.275 AC: 953 AN: 3478

EpiCase AF: 0.358

EpiControl AF: 0.354

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2021	This variant is associated with the following publications: (PMID: 19079261, 21912638, 23818875, 24971614, 23270367) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Benign	0.34
DEOGEN2	Benign	0.056	T;.;T;T;.;T;.;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.014	.;.;T;T;T;T;T;T
MetaRNN	Benign	0.00064	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N;N;.;N;N;.;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.050	N;N;N;.;N;N;N;N
REVEL	Benign	0.030
Sift	Benign	1.0	T;T;T;.;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B;B;.
Vest4		0.015
MPC		0.23
ClinPred		0.0021	T
GERP RS		3.1
Varity_R		0.018
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7498665; hg19: chr16-28883241; COSMIC: COSV59461486; COSMIC: COSV59461486;