Genetic Variant SHC3:p.Glu497Lys (chr9-89038160-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_016848.6(SHC3):c.1489G>A(p.Glu497Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00307 in 1,614,028 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 16 hom. )

Consequence

SHC3
NM_016848.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.00

Variant links:

Genes affected

SHC3 (HGNC:18181): (SHC adaptor protein 3) Enables phosphotyrosine residue binding activity. Predicted to be involved in transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to act upstream of or within glutamatergic synaptic transmission and learning or memory. Predicted to be located in cytosol. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SHC3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009997219).

BP6

Variant 9-89038160-C-T is Benign according to our data. Variant chr9-89038160-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 710663.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 332 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHC3	NM_016848.6 link	c.1489G>A	p.Glu497Lys	missense_variant	Exon 11 of 12	ENST00000375835.9	NP_058544.3	Q92529-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHC3	ENST00000375835.9 link	c.1489G>A	p.Glu497Lys	missense_variant	Exon 11 of 12	1	NM_016848.6	ENSP00000364995.4		Q92529-1
SHC3	ENST00000375831.1 link	c.133G>A	p.Glu45Lys	missense_variant	Exon 2 of 3	2		ENSP00000364991.1		Q5T7I8

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

332

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00340

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00362

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00298

AC:

749

AN:

251486

Hom.:

AF XY:

0.00337

AC XY:

458

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000347

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00559

Gnomad FIN exome

AF:

0.00351

Gnomad NFE exome

AF:

0.00408

Gnomad OTH exome

AF:

0.00309

GnomAD4 exome

AF:

0.00316

AC:

4621

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00330

AC XY:

2401

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00601

Gnomad4 FIN exome

AF:

0.00337

Gnomad4 NFE exome

AF:

0.00335

Gnomad4 OTH exome

AF:

0.00242

GnomAD4 genome

AF:

0.00218

AC:

332

AN:

152138

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

167

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.000458

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00333

Gnomad4 FIN

AF:

0.00340

Gnomad4 NFE

AF:

0.00362

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00290

Hom.:

Bravo

AF:

0.00186

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00345

AC:

419

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00289

EpiControl

AF:

0.00338

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

D;T

Eigen

Benign

-0.053

Eigen_PC

Benign

-0.091

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.81

T;T

M_CAP

Benign

0.065

MetaRNN

Benign

0.010

T;T

MetaSVM

Benign

-0.71

MutationAssessor

Pathogenic

3.0

M;.

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.25

Sift

Uncertain

0.0010

D;T

Sift4G

Uncertain

0.046

D;D

Polyphen

0.93

P;.

Vest4

0.30

MVP

0.72

MPC

0.62

ClinPred

0.072

GERP RS

3.3

Varity_R

0.34

gMVP

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over