rs7498665

Variant names:

• chr16-28871920-A-G
• rs7498665
• NM_001387430.1:c.1450A>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T484G) has been classified as Uncertain significance.

• 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
• Publications: 248 publications found

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]

SH2B1 Gene-Disease associations (from GenCC):

• severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387430.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B1	NM_001387430.1	MANE Select	c.1450A>G	p.Thr484Ala	missense	Exon 5 of 8	NP_001374359.1
	SH2B1	NM_001145795.2		c.1450A>G	p.Thr484Ala	missense	Exon 6 of 9	NP_001139267.1
	SH2B1	NM_001308293.2		c.1450A>G	p.Thr484Ala	missense	Exon 8 of 11	NP_001295222.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SH2B1	ENST00000684370.1	MANE Select	c.1450A>G	p.Thr484Ala	missense	Exon 5 of 8	ENSP00000507475.1
	SH2B1	ENST00000618521.4	TSL:1	c.1450A>G	p.Thr484Ala	missense	Exon 6 of 9	ENSP00000481709.1
	SH2B1	ENST00000359285.10	TSL:1	c.1450A>G	p.Thr484Ala	missense	Exon 6 of 10	ENSP00000352232.5

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

GnomAD2 exomes AF: 0.351 AC: 87551 AN: 249400 AF XY: 0.343

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 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

African (AFR) AF: 0.261 AC: 8475 AN: 32430

American (AMR) AF: 0.493 AC: 21814 AN: 44274

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 7003 AN: 25150

East Asian (EAS) AF: 0.141 AC: 5038 AN: 35640

South Asian (SAS) AF: 0.228 AC: 19534 AN: 85530

European-Finnish (FIN) AF: 0.436 AC: 22499 AN: 51612

Middle Eastern (MID) AF: 0.209 AC: 1162 AN: 5552

European-Non Finnish (NFE) AF: 0.400 AC: 432418 AN: 1081110

Other (OTH) AF: 0.352 AC: 20535 AN: 58322

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

African (AFR) AF: 0.270 AC: 10595 AN: 39206

American (AMR) AF: 0.409 AC: 6066 AN: 14830

Ashkenazi Jewish (ASJ) AF: 0.270 AC: 920 AN: 3406

East Asian (EAS) AF: 0.124 AC: 580 AN: 4668

South Asian (SAS) AF: 0.227 AC: 1009 AN: 4436

European-Finnish (FIN) AF: 0.433 AC: 4272 AN: 9868

Middle Eastern (MID) AF: 0.228 AC: 66 AN: 290

European-Non Finnish (NFE) AF: 0.395 AC: 26279 AN: 66528

Other (OTH) AF: 0.313 AC: 637 AN: 2032

Alfa AF: 0.359 Hom.: 7523

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19079261, 21912638, 23818875, 24971614, 23270367)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.014	T
MetaRNN	Benign	0.00064	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.43
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.23
ClinPred		0.0021	T
GERP RS		3.1
PromoterAI		-0.029	Neutral
Varity_R		0.018
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7498665; hg19: chr16-28883241; COSMIC: COSV59461486; COSMIC: COSV59461486;