Variant 15-48856094-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_203349.4(SHC4):c.1101G>C(p.Glu367Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,288 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 6.8e-7 ( 0 hom. )

Consequence

SHC4
NM_203349.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.247

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10100326).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SHC4	NM_203349.4 linkuse as main transcript	c.1101G>C	p.Glu367Asp	missense_variant	8/12	ENST00000332408.9
SHC4	XM_005254375.4 linkuse as main transcript	c.552G>C	p.Glu184Asp	missense_variant	8/12
SHC4	XM_047432492.1 linkuse as main transcript	c.243G>C	p.Glu81Asp	missense_variant	5/9
SHC4	XM_047432493.1 linkuse as main transcript	c.243G>C	p.Glu81Asp	missense_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHC4	ENST00000332408.9 linkuse as main transcript	c.1101G>C	p.Glu367Asp	missense_variant	8/12	1	NM_203349.4	P1	Q6S5L8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461288

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726910

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Apr 12, 2023

The c.1101G>C (p.E367D) alteration is located in exon 8 (coding exon 8) of the SHC4 gene. This alteration results from a G to C substitution at nucleotide position 1101, causing the glutamic acid (E) at amino acid position 367 to be replaced by an aspartic acid (D). 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

0.084

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

Cadd

Benign

6.3

Dann

Benign

0.95

DEOGEN2

Benign

0.089

T;.;T;.

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.16

T;T;T;T

M_CAP

Benign

0.0035

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.91

N;N;N;N

REVEL

Benign

0.035

Sift

Benign

0.18

T;T;T;.

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.0010

B;B;.;.

Vest4

0.093

MutPred

0.15

Loss of solvent accessibility (P = 0.1177);.;.;.;

MVP

0.52

MPC

0.12

ClinPred

0.085

GERP RS

-1.6

Varity_R

0.057

gMVP

0.28

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over