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

Variant summary

Our verdict is Benign. The variant received -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. 13/22 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

Publications

7 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 710663.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 332 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016848.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHC3	NM_016848.6	MANE Select	c.1489G>A	p.Glu497Lys	missense	Exon 11 of 12	NP_058544.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHC3	ENST00000375835.9	TSL:1 MANE Select	c.1489G>A	p.Glu497Lys	missense	Exon 11 of 12	ENSP00000364995.4	Q92529-1
	SHC3	ENST00000375831.1	TSL:2	c.133G>A	p.Glu45Lys	missense	Exon 2 of 3	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

GnomAD2 exomes

AF:

0.00298

AC:

749

AN:

251486

AF XY:

0.00337

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 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

African (AFR)

AF:

0.000478

AC:

AN:

33480

American (AMR)

AF:

0.000402

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000344

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00601

AC:

518

AN:

86258

European-Finnish (FIN)

AF:

0.00337

AC:

180

AN:

53416

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00335

AC:

3725

AN:

1112012

Other (OTH)

AF:

0.00242

AC:

146

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

325

651

976

1302

1627

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00218

AC:

332

AN:

152138

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

167

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41478

American (AMR)

AF:

0.000523

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.00333

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00340

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00362

AC:

246

AN:

68010

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00284

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

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.54

Eigen

Benign

-0.053

Eigen_PC

Benign

-0.091

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.81

M_CAP

Benign

0.065

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.71

MutationAssessor

Pathogenic

3.0

PhyloP100

5.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.25

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.046

Polyphen

0.93

Vest4

0.30

MVP

0.72

MPC

0.62

ClinPred

0.072

GERP RS

3.3

Varity_R

0.34

gMVP

0.65

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over