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: 250 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

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

• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).
• BP6: ClinVar 2-star benign — strong (BP6); ClinVar germline classification: Benign/Likely Benign, 2 star(s).
• BA1: 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	NP_001374359.1	Q9NRF2-1
	SH2B1	NM_001145795.2		c.1450A>G	p.Thr484Ala	missense	Exon 6 of 9	NP_001139267.1	Q9NRF2-1
	SH2B1	NM_001308293.2		c.1450A>G	p.Thr484Ala	missense	Exon 8 of 11	NP_001295222.1	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	ENSP00000507475.1	Q9NRF2-1
	SH2B1	ENST00000618521.4	TSL:1	c.1450A>G	p.Thr484Ala	missense	Exon 6 of 9	ENSP00000481709.1	Q9NRF2-1
	SH2B1	ENST00000359285.10	TSL:1	c.1450A>G	p.Thr484Ala	missense	Exon 6 of 10	ENSP00000352232.5	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	0.346	50546	9247	146026	23
GnomAD2 exomes	0.351	87551		249400
GnomAD4 exome	0.379	538478	105062	1419620	30
GnomAD4 genome	0.346	50639	9276	146154	23
TOPMed (Bravo)	0.339
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.355	43155	8150	121454
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	0.329	771	116	2342
ChinaMAP Phase 1	0.120
Denmark Genome	0.407	122		300
ESP6500 (Exome Variant Server)	0.344	4468		12994
GenomeAsia100K	0.275	953		3478
Korea4K (4,157 Koreans)	0.123	891		7220
Qatari Genome	0.179	350		1950
Turkish Variome	0.294	1931	290	6564
UK10K	0.398	3013		7562

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 prediction	Prediction	Score
AlphaGenome AVI	Uncertain	-	16
AlphaMissense	Benign	-	0.047
BayesDel_addAF	Benign	T	-0.79
BayesDel_noAF	Benign	-	-0.76
CADD	Benign	-	15
DANN	Benign	-	0.34
DEOGEN2	Benign	T	0.056
Eigen	Benign	-	-0.93
Eigen_PC	Benign	-	-0.75
FATHMM_MKL	Benign	N	0.0092
FuncVEP CTI	Benign	-	0.00060
GPN-Star LLR	N/A	-	7.3
GPN-Star score	N/A	-	3.4
LIST_S2	Benign	T	0.014
MetaRNN	Benign	T	0.00064
MetaSVM	Benign	T	-0.93
Mutation Taster	N/A	polymorphism (auto)	100/0
MutationAssessor	Benign	N	0.0
PhyloP100	Benign	-	0.43
popEVE	Benign	-	-2.7
PrimateAI	Uncertain	T	0.53
PromoterAI	N/A	Neutral	-0.029
PROVEAN	Benign	N	0.050
REVEL	Benign	-	0.030
Sift	Benign	T	1.0
Sift4G	Benign	T	1.0
Varity_R	N/A	-	0.018
VESM-3B	Benign	-	-1.6

Showing 28 of 28 scores

Splicing Scores

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

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.

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