X-141906113-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005462.5(MAGEC1):c.709G>A(p.Val237Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 88,029 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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 0.00045 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.00029 (6 hom. 47 hem.)
  • Failed GnomAD Quality Control
• Consequence: MAGEC1 NM_005462.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.432

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02742052).
• BS2: High Hemizygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGEC1	NM_005462.5	c.709G>A	p.Val237Met	missense_variant	4/4	ENST00000285879.5
MAGEC1	XM_011531418.3	c.709G>A	p.Val237Met	missense_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGEC1	ENST00000285879.5	c.709G>A	p.Val237Met	missense_variant	4/4	1	NM_005462.5	P3
MAGEC1	ENST00000406005.2	c.-115+566G>A		intron_variant		1		A2

Frequencies

GnomAD3 genomes AF: 0.000455 AC: 40 AN: 87976 Hom.: 0 Cov.: 22 AF XY: 0.0000803 AC XY: 2 AN XY: 24904

Gnomad AFR AF: 0.000630

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000570

Gnomad ASJ AF: 0.000941

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000522

Gnomad FIN AF: 0.000221

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000346

Gnomad OTH AF: 0.000830

GnomAD3 exomes AF: 0.000168 AC: 29 AN: 172295 Hom.: 0 AF XY: 0.0000665 AC XY: 4 AN XY: 60177

Gnomad AFR exome AF: 0.000963

Gnomad AMR exome AF: 0.0000377

Gnomad ASJ exome AF: 0.000725

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000574

Gnomad FIN exome AF: 0.0000660

Gnomad NFE exome AF: 0.000118

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000289 AC: 214 AN: 740243 Hom.: 6 Cov.: 41 AF XY: 0.000221 AC XY: 47 AN XY: 212477

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.000497

Gnomad4 ASJ exome AF: 0.000626

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000238

Gnomad4 FIN exome AF: 0.0000293

Gnomad4 NFE exome AF: 0.000248

Gnomad4 OTH exome AF: 0.000295

GnomAD4 genome AF: 0.000454 AC: 40 AN: 88029 Hom.: 0 Cov.: 22 AF XY: 0.0000801 AC XY: 2 AN XY: 24959

Gnomad4 AFR AF: 0.000628

Gnomad4 AMR AF: 0.000570

Gnomad4 ASJ AF: 0.000941

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000525

Gnomad4 FIN AF: 0.000221

Gnomad4 NFE AF: 0.000346

Gnomad4 OTH AF: 0.000818

Alfa AF: 0.000927 Hom.: 3

ExAC AF: 0.000562 AC: 48

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.709G>A (p.V237M) alteration is located in exon 4 (coding exon 2) of the MAGEC1 gene. This alteration results from a G to A substitution at nucleotide position 709, causing the valine (V) at amino acid position 237 to be replaced by a methionine (M). 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	0.44
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	14
Dann	Benign	0.84
DEOGEN2	Benign	0.0060	T
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.059
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.031	D
Polyphen		0.31	B
Vest4		0.058
MVP		0.067
ClinPred		0.018	T
Varity_R		0.083
gMVP		0.013

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

Other links and lift over

dbSNP: rs146512531; hg19: chrX-140993899;