15-48851226-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_203349.4(SHC4):c.1265G>A(p.Ser422Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,778 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000023 ( 1 hom. )

Consequence

SHC4
NM_203349.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.96

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06451595).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SHC4	NM_203349.4 linkuse as main transcript	c.1265G>A	p.Ser422Asn	missense_variant	9/12	ENST00000332408.9
SHC4	XM_005254375.4 linkuse as main transcript	c.716G>A	p.Ser239Asn	missense_variant	9/12
SHC4	XM_047432492.1 linkuse as main transcript	c.407G>A	p.Ser136Asn	missense_variant	6/9
SHC4	XM_047432493.1 linkuse as main transcript	c.407G>A	p.Ser136Asn	missense_variant	7/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHC4	ENST00000332408.9 linkuse as main transcript	c.1265G>A	p.Ser422Asn	missense_variant	9/12	1	NM_203349.4	P1	Q6S5L8-1
SHC4	ENST00000396535.7 linkuse as main transcript	c.536G>A	p.Ser179Asn	missense_variant	6/9	1			Q6S5L8-2
SHC4	ENST00000537958.5 linkuse as main transcript	c.407G>A	p.Ser136Asn	missense_variant	7/10	2
SHC4	ENST00000557797.5 linkuse as main transcript	c.384+4727G>A		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251266

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135798

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:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000494

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 20, 2021

The c.1265G>A (p.S422N) alteration is located in exon 9 (coding exon 9) of the SHC4 gene. This alteration results from a G to A substitution at nucleotide position 1265, causing the serine (S) at amino acid position 422 to be replaced by an asparagine (N). 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

0.099

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.58

Cadd

Benign

Dann

Uncertain

0.98

DEOGEN2

Benign

0.043

T;.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.044

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.63

T;T;T

M_CAP

Benign

0.0026

MetaRNN

Benign

0.065

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

0.37

N;N;N

REVEL

Benign

0.021

Sift

Benign

0.50

T;T;T

Sift4G

Benign

0.68

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.17

MutPred

0.38

Gain of relative solvent accessibility (P = 0.0479);.;.;

MVP

0.42

MPC

0.13

ClinPred

0.061

GERP RS

5.1

Varity_R

0.085

gMVP

0.27

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