rs7498665

Variant names:

• chr16-28871920-A-G
• rs7498665
• NM_001387430.1:c.1450A>G
• SH2B1 p.Thr484Ala

Your query was ambiguous. Multiple possible variants found:

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

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6_Strong

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 cumulative frequency of 0.376 (AC=589,117) in the gnomAD database across 1,565,774 control chromosomes, including 114,338 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.487. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T484G: Uncertain_significance (ClinVar VariationId 3350075, 0 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• 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: 2 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: AR, AD Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: LiferaOmics, Orphanet, Genomics England PanelApp

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.4872 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	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	Prot: NP_001374359.1 UniProt:
	SH2B1 NM_001145795.2		c.1450A>G p.Thr484Ala	missense	Exon 6 of 9	Prot: NP_001139267.1 UniProt:
	SH2B1 NM_001308293.2		c.1450A>G p.Thr484Ala	missense	Exon 8 of 11	Prot: NP_001295222.1 UniProt:

SH2B1 NM_001387430.1

MANE Select

HGVSc / HGVSpc.1450A>Gp.Thr484Ala

Exon rankExon 5 of 8

missense

Prot: NP_001374359.1UniProt: Q9NRF2-1

SH2B1 NM_001145795.2

HGVSc / HGVSpc.1450A>Gp.Thr484Ala

Exon rankExon 6 of 9

missense

Prot: NP_001139267.1UniProt: Q9NRF2-1

SH2B1 NM_001308293.2

HGVSc / HGVSpc.1450A>Gp.Thr484Ala

Exon rankExon 8 of 11

missense

Prot: NP_001295222.1UniProt: Q9NRF2-1

Ensembl Transcripts

Sel.	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	Prot: ENSP00000507475.1 UniProt:
	SH2B1 ENST00000618521.4	TSL:1	c.1450A>G p.Thr484Ala	missense	Exon 6 of 9	Prot: ENSP00000481709.1 UniProt:
	SH2B1 ENST00000359285.10	TSL:1	c.1450A>G p.Thr484Ala	missense	Exon 6 of 10	Prot: ENSP00000352232.5 UniProt:

SH2B1 ENST00000684370.1

MANE Select

HGVSc / HGVSpc.1450A>Gp.Thr484Ala

Exon rankExon 5 of 8

missense

Prot: ENSP00000507475.1UniProt: Q9NRF2-1

SH2B1 ENST00000618521.4

TSL:1

HGVSc / HGVSpc.1450A>Gp.Thr484Ala

Exon rankExon 6 of 9

missense

Prot: ENSP00000481709.1UniProt: Q9NRF2-1

SH2B1 ENST00000359285.10

TSL:1

HGVSc / HGVSpc.1450A>Gp.Thr484Ala

Exon rankExon 6 of 10

missense

Prot: ENSP00000352232.5UniProt: Q9NRF2-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.346	AC:50546	Hom:9247	AN:146026	Cov:23
GnomAD2 exomes	AF: 0.351	AC:87551	Hom:	AN:249400	Cov:
GnomAD4 exome	AF: 0.379	AC:538478	Hom:105062	AN:1419620	Cov:30
GnomAD4 genome	AF: 0.346	AC:50639	Hom:9276	AN:146154	Cov:23
TOPMed (Bravo)	AF: 0.339	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.355	AC:43155	Hom:8150	AN:121454	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.329	AC:771	Hom:116	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.120	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.407	AC:122	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.344	AC:4468	Hom:	AN:12994	Cov:
GenomeAsia100K	AF: 0.275	AC:953	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.123	AC:891	Hom:	AN:7220	Cov:
Qatari Genome	AF: 0.179	AC:350	Hom:	AN:1950	Cov:
Turkish Variome	AF: 0.294	AC:1931	Hom:290	AN:6564	Cov:
UK10K	AF: 0.398	AC:3013	Hom:	AN:7562	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.414 *	4570	11042	0.413 *	7250	17548
BipEx(Bipolar disorder (including schizoaffective))	0.403	11461	28414	0.392	11297	28838
Epi25(Epilepsy)	0.351	14247	40564	0.388	24862	64048
SCHEMA(Schizophrenia)	0.291	22457	77068	0.307	42588	138700

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
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
FuncVEP CTI	Benign	0.00060
GPN-Star LLR	N/A	7.3
GPN-Star score	N/A	3.4
LIST_S2	Benign	0.014	T
MetaRNN	Benign	0.00064	T
MetaSVM	Benign	-0.93	T
Mutation Taster	N/A	100/0	polymorphism (auto)
MutationAssessor	Benign	0.0	N
PhyloP100	Benign	0.43
popEVE	Benign	-2.7
PrimateAI	Uncertain	0.53	T
PromoterAI	N/A	-0.029	Neutral
PROVEAN	Benign	0.050	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R	N/A	0.018
VESM-3B	Benign	-1.6

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs7498665;

hg19: chr16-28883241;

COSMIC: COSV59461486;

COSMIC: COSV59461486;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar