15-48843498-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_203349.4(SHC4):c.1394A>G(p.Tyr465Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000118 in 1,614,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SHC4
NM_203349.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.32

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 5 ACMG points.

PM1

In a mutagenesis_site Remains phosphorylated. Contains a residual phosphorylation; when associated with 374-F-F-375. Reduced the phosphorylation in presence of MUSK; when associated with 374-F-F-375 and 424. Completely abolishes the phosphorylation in presence of MUSK; when associated with 374-F-F-375; F-403; F-413 and F-424. Retains the ability to bind MUSK. Retains the ability to bind MUSK; when associated with 374-F-F-375. Retains the ability to bind MUSK; when associated with 374-F-F-375 and F-424. Retains the ability to bind MUSK; when associated with 374-F-F-375; F-403; F-413 and F-424. (size 0) in uniprot entity SHC4_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.79

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SHC4	NM_203349.4 linkuse as main transcript	c.1394A>G	p.Tyr465Cys	missense_variant	10/12	ENST00000332408.9
SHC4	XM_005254375.4 linkuse as main transcript	c.845A>G	p.Tyr282Cys	missense_variant	10/12
SHC4	XM_047432492.1 linkuse as main transcript	c.536A>G	p.Tyr179Cys	missense_variant	7/9
SHC4	XM_047432493.1 linkuse as main transcript	c.536A>G	p.Tyr179Cys	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHC4	ENST00000332408.9 linkuse as main transcript	c.1394A>G	p.Tyr465Cys	missense_variant	10/12	1	NM_203349.4	P1	Q6S5L8-1
SHC4	ENST00000396535.7 linkuse as main transcript	c.665A>G	p.Tyr222Cys	missense_variant	7/9	1			Q6S5L8-2
SHC4	ENST00000537958.5 linkuse as main transcript	c.536A>G	p.Tyr179Cys	missense_variant	8/10	2
SHC4	ENST00000557797.5 linkuse as main transcript	c.*40A>G		3_prime_UTR_variant, NMD_transcript_variant	6/7	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251214

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135758

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000869

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

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

Dec 09, 2023

The c.1394A>G (p.Y465C) alteration is located in exon 10 (coding exon 10) of the SHC4 gene. This alteration results from a A to G substitution at nucleotide position 1394, causing the tyrosine (Y) at amino acid position 465 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

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.;T

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.79

D;D;D

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.5

M;.;.

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-7.2

D;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.82

MutPred

0.46

Gain of disorder (P = 0.0163);.;.;

MVP

0.75

MPC

0.64

ClinPred

0.99

GERP RS

5.0

Varity_R

0.63

gMVP

0.68

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