Variant 15-48851220-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_203349.4(SHC4):c.1271A>G(p.Tyr424Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

SHC4
NM_203349.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.54

Variant links:

Genes affected

SHC4 (HGNC:16743): (SHC adaptor protein 4) Predicted to enable receptor tyrosine kinase binding activity. Predicted to be involved in transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to act upstream of or within several processes, including apoptotic process; positive regulation of cell population proliferation; and stem cell differentiation. Predicted to be located in postsynaptic membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

SHC4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a modified_residue Phosphotyrosine (size 0) in uniprot entity SHC4_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SHC4	NM_203349.4 linkuse as main transcript	c.1271A>G	p.Tyr424Cys	missense_variant	9/12	ENST00000332408.9	NP_976224.3
SHC4	XM_005254375.4 linkuse as main transcript	c.722A>G	p.Tyr241Cys	missense_variant	9/12		XP_005254432.1
SHC4	XM_047432492.1 linkuse as main transcript	c.413A>G	p.Tyr138Cys	missense_variant	6/9		XP_047288448.1
SHC4	XM_047432493.1 linkuse as main transcript	c.413A>G	p.Tyr138Cys	missense_variant	7/10		XP_047288449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHC4	ENST00000332408.9 linkuse as main transcript	c.1271A>G	p.Tyr424Cys	missense_variant	9/12	1	NM_203349.4	ENSP00000329668	P1	Q6S5L8-1
SHC4	ENST00000396535.7 linkuse as main transcript	c.542A>G	p.Tyr181Cys	missense_variant	6/9	1		ENSP00000379786		Q6S5L8-2
SHC4	ENST00000537958.5 linkuse as main transcript	c.413A>G	p.Tyr138Cys	missense_variant	7/10	2		ENSP00000443300
SHC4	ENST00000557797.5 linkuse as main transcript	c.384+4733A>G		intron_variant, NMD_transcript_variant		3		ENSP00000453344

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251242

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2023

The c.1271A>G (p.Y424C) alteration is located in exon 9 (coding exon 9) of the SHC4 gene. This alteration results from a A to G substitution at nucleotide position 1271, causing the tyrosine (Y) at amino acid position 424 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.14

T;.;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.020

MetaRNN

Uncertain

0.63

D;D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;.

MutationTaster

Benign

0.99

N;N;N

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.17

Sift

Benign

0.14

T;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

1.0

D;D;.

Vest4

0.81

MutPred

0.40

Gain of disorder (P = 0.0519);.;.;

MVP

0.60

MPC

0.67

ClinPred

0.83

GERP RS

5.1

Varity_R

0.15

gMVP

0.38

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

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