Genetic Variant NM_005462.5:c.661A>G (chrX-141906065-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005462.5(MAGEC1):c.661A>G(p.Thr221Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., 0 hem., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. 10 hem. )

Failed GnomAD Quality Control

Consequence

MAGEC1
NM_005462.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.15

Variant links:

Genes affected

MAGEC1 (HGNC:6812): (MAGE family member C1) This gene is a member of the melanoma antigen gene (MAGE) family. The proteins of this family are tumor-specific antigens that can be recognized by autologous cytolytic T lymphocytes. This protein contains a large number of unique short repetitive sequences in front of the MAGE-homologous sequence, and therefore is about 800 aa longer than the other MAGE proteins. [provided by RefSeq, Jul 2008]

MAGEC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041446567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEC1	NM_005462.5 link	c.661A>G	p.Thr221Ala	missense_variant	Exon 4 of 4	ENST00000285879.5	NP_005453.2	O60732-1
MAGEC1	XM_011531418.3 link	c.661A>G	p.Thr221Ala	missense_variant	Exon 4 of 4		XP_011529720.1	O60732-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEC1	ENST00000285879.5 link	c.661A>G	p.Thr221Ala	missense_variant	Exon 4 of 4	1	NM_005462.5	ENSP00000285879.4		O60732-1
MAGEC1	ENST00000406005.2 link	c.-115+518A>G		intron_variant	Intron 3 of 3	1		ENSP00000385500.2		O60732-2

Frequencies

GnomAD3 genomes

AF:

0.0000196

AC:

AN:

101887

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31773

show subpopulations

Gnomad AFR

AF:

0.0000350

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:

0.0000209

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000170

AC:

AN:

176529

Hom.:

AF XY:

0.0000319

AC XY:

AN XY:

62599

show subpopulations

Gnomad AFR exome

AF:

0.0000777

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000180

AC:

AN:

1001619

Hom.:

Cov.:

100

AF XY:

0.0000298

AC XY:

AN XY:

335119

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:

0.000101

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000157

Gnomad4 OTH exome

AF:

0.0000235

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000196

AC:

AN:

101929

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

31823

show subpopulations

Gnomad4 AFR

AF:

0.0000349

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:

0.0000209

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000132

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.661A>G (p.T221A) alteration is located in exon 4 (coding exon 2) of the MAGEC1 gene. This alteration results from a A to G substitution at nucleotide position 661, causing the threonine (T) at amino acid position 221 to be replaced by an alanine (A). 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

0.18

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-1.0

CADD

Benign

1.8

DANN

Benign

0.16

DEOGEN2

Benign

0.0041

FATHMM_MKL

Benign

0.0098

LIST_S2

Benign

0.22

M_CAP

Benign

0.0025

MetaRNN

Benign

0.041

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.1

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.050

REVEL

Benign

0.0070

Sift

Uncertain

0.020

Sift4G

Uncertain

0.038

Polyphen

0.0040

Vest4

0.0080

MutPred

0.14

Gain of helix (P = 0.0199);

MVP

0.048

ClinPred

0.013

Varity_R

0.052

gMVP

0.017

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