X-151924163-G-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001011548.1(MAGEA4):c.499G>T(p.Val167Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000051 in 1,098,106 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.000051 ( 0 hom. 12 hem. )

Failed GnomAD Quality Control

Consequence

MAGEA4
NM_001011548.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.338

Variant links:

Genes affected

MAGEA4 (HGNC:6802): (MAGE family member A4) This gene is a member of the MAGEA gene family. The members of this family encode proteins with 50 to 80% sequence identity to each other. The promoters and first exons of the MAGEA genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls. The MAGEA genes are clustered at chromosomal location Xq28. They have been implicated in some hereditary disorders, such as dyskeratosis congenita. Several variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

MAGEA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11590731).

BS2

High Hemizygotes in GnomAdExome4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA4	NM_001011548.1 link	c.499G>T	p.Val167Leu	missense_variant	Exon 3 of 3	ENST00000276344.6	NP_001011548.1	P43358A0A024RC12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEA4	ENST00000276344.6 link	c.499G>T	p.Val167Leu	missense_variant	Exon 3 of 3	2	NM_001011548.1	ENSP00000276344.2		P43358

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

112367

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34525

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000751

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000273

AC:

AN:

183397

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

67853

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:

0.0000611

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000510

AC:

AN:

1098106

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

363474

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:

0.0000665

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000356

AC:

AN:

112367

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34525

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000751

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.499G>T (p.V167L) alteration is located in exon 3 (coding exon 1) of the MAGEA4 gene. This alteration results from a G to T substitution at nucleotide position 499, causing the valine (V) at amino acid position 167 to be replaced by a leucine (L). 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

0.25

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.99

DANN

Benign

0.84

DEOGEN2

Benign

0.055

T;T;.;T;.;.;T;.;.;.;T;T;T;.

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.74

T;T;.;.;.;.;.;T;T;.;.;.;.;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.12

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.27

.;N;.;N;.;.;N;.;.;.;N;N;N;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.4

N;N;N;N;D;D;N;N;N;D;N;N;N;D

REVEL

Benign

0.074

Sift

Benign

0.13

T;T;T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.13

T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.11

.;B;.;B;.;.;B;.;.;.;B;B;B;.

Vest4

0.35

MutPred

0.64

Gain of catalytic residue at V167 (P = 0.0373);Gain of catalytic residue at V167 (P = 0.0373);Gain of catalytic residue at V167 (P = 0.0373);Gain of catalytic residue at V167 (P = 0.0373);Gain of catalytic residue at V167 (P = 0.0373);Gain of catalytic residue at V167 (P = 0.0373);Gain of catalytic residue at V167 (P = 0.0373);Gain of catalytic residue at V167 (P = 0.0373);Gain of catalytic residue at V167 (P = 0.0373);Gain of catalytic residue at V167 (P = 0.0373);Gain of catalytic residue at V167 (P = 0.0373);Gain of catalytic residue at V167 (P = 0.0373);Gain of catalytic residue at V167 (P = 0.0373);Gain of catalytic residue at V167 (P = 0.0373);

MVP

0.15

MPC

0.0037

ClinPred

0.037

GERP RS

-0.91

Varity_R

0.24

gMVP

0.16

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