Genetic Variant NM_001011548.1:c.423C>G (chrX-151924087-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001011548.1(MAGEA4):c.423C>G(p.Ile141Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000455 in 1,098,186 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I141V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0000046 ( 0 hom. 0 hem. )

Consequence

MAGEA4
NM_001011548.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.158

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1641961).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001011548.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAGEA4	NM_001011548.1	MANE Select	c.423C>G	p.Ile141Met	missense	Exon 3 of 3	NP_001011548.1	P43358
MAGEA4	NM_001011549.1		c.423C>G	p.Ile141Met	missense	Exon 3 of 3	NP_001011549.1	P43358
MAGEA4	NM_001011550.1		c.423C>G	p.Ile141Met	missense	Exon 3 of 3	NP_001011550.1	P43358

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAGEA4	ENST00000276344.6	TSL:2 MANE Select	c.423C>G	p.Ile141Met	missense	Exon 3 of 3	ENSP00000276344.2	P43358
MAGEA4	ENST00000360243.6	TSL:1	c.423C>G	p.Ile141Met	missense	Exon 3 of 3	ENSP00000353379.2	P43358
MAGEA4	ENST00000370335.5	TSL:1	c.423C>G	p.Ile141Met	missense	Exon 3 of 3	ENSP00000359360.1	P43358

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

183435

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000455

AC:

AN:

1098186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363552

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26402

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40481

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000594

AC:

AN:

842126

Other (OTH)

AF:

0.00

AC:

AN:

46098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.88

CADD

Benign

6.2

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.044

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.14

M_CAP

Benign

0.0027

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.1

PhyloP100

-0.16

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.7

REVEL

Benign

0.032

Sift

Benign

0.11

Sift4G

Benign

0.075

Polyphen

0.11

Vest4

0.12

MutPred

0.70

Loss of methylation at K142 (P = 0.0263)

MVP

0.068

MPC

0.0048

ClinPred

0.036

GERP RS

-0.33

Varity_R

0.57

gMVP

0.17

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over