Genetic Variant NM_005362.4:c.370T>C (chrX-152701202-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

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

The NM_005362.4(MAGEA3):c.370T>C(p.Tyr124His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000897 in 111,421 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 21)

Consequence

MAGEA3
NM_005362.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.292

Variant links:

Genes affected

MAGEA3 (HGNC:6801): (MAGE family member A3) 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. [provided by RefSeq, Jul 2008]

MAGEA3 links:

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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, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA3	NM_005362.4 link	c.370T>C	p.Tyr124His	missense_variant	Exon 3 of 3	ENST00000370278.4	NP_005353.1	P43357

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAGEA3	ENST00000370278.4 link	c.370T>C	p.Tyr124His	missense_variant	Exon 3 of 3	1	NM_005362.4	ENSP00000359301.3	P43357
MAGEA3	ENST00000598245.2 link	c.370T>C	p.Tyr124His	missense_variant	Exon 3 of 3	2		ENSP00000473093.1	P43357
MAGEA3	ENST00000417212.5 link	c.370T>C	p.Tyr124His	missense_variant	Exon 3 of 3	2		ENSP00000392758.1	E7EMU0

Frequencies

GnomAD3 genomes

AF:

0.00000897

AC:

AN:

111421

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33655

show subpopulations

Gnomad AFR

AF:

0.0000327

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000897

AC:

AN:

111421

Hom.:

Cov.:

AF XY:

0.0000297

AC XY:

AN XY:

33655

show subpopulations

Gnomad4 AFR

AF:

0.0000327

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

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.370T>C (p.Y124H) alteration is located in exon 3 (coding exon 1) of the MAGEA3 gene. This alteration results from a T to C substitution at nucleotide position 370, causing the tyrosine (Y) at amino acid position 124 to be replaced by a histidine (H). 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

Pathogenic

0.59

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.61

D;T;D

FATHMM_MKL

Benign

0.083

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Benign

0.0012

MetaRNN

Pathogenic

0.87

D;D;D

MetaSVM

Benign

-1.1

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.7

D;D;.

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.026

D;D;D

Vest4

0.28

MutPred

0.82

Gain of disorder (P = 0.0292);Gain of disorder (P = 0.0292);Gain of disorder (P = 0.0292);

MVP

0.57

ClinPred

1.0

GERP RS

0.60

Varity_R

0.84

gMVP

0.40

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

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