Variant 1-154489194-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001010846.3(SHE):c.881A>G(p.Tyr294Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,990 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 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

SHE
NM_001010846.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.53

Variant links:

Genes affected

SHE (HGNC:27004): (Src homology 2 domain containing E) Predicted to enable phosphotyrosine residue binding activity. [provided by Alliance of Genome Resources, Apr 2022]

SHE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SHE	NM_001010846.3 linkuse as main transcript	c.881A>G	p.Tyr294Cys	missense_variant	3/6	ENST00000304760.3
SHE	XM_011509163.4 linkuse as main transcript	c.881A>G	p.Tyr294Cys	missense_variant	3/7
SHE	XM_005244891.6 linkuse as main transcript	c.881A>G	p.Tyr294Cys	missense_variant	3/6
SHE	NR_135169.2 linkuse as main transcript	n.1267A>G		non_coding_transcript_exon_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHE	ENST00000304760.3 linkuse as main transcript	c.881A>G	p.Tyr294Cys	missense_variant	3/6	1	NM_001010846.3	P1
SHE	ENST00000555188.5 linkuse as main transcript			upstream_gene_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000159

AC:

AN:

251260

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135864

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000450

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.000362

Gnomad4 AMR

AF:

0.00

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

Alfa

AF:

0.0000954

Hom.:

Bravo

AF:

0.000159

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

Mar 17, 2023

The c.881A>G (p.Y294C) alteration is located in exon 3 (coding exon 3) of the SHE gene. This alteration results from a A to G substitution at nucleotide position 881, causing the tyrosine (Y) at amino acid position 294 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

0.46

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Uncertain

0.050

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.87

MetaSVM

Benign

-0.50

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-6.5

REVEL

Uncertain

0.38

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.87

MVP

0.54

MPC

1.4

ClinPred

0.99

GERP RS

5.3

Varity_R

0.76

gMVP

0.54

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