X-51895314-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006986.4(MAGED1):c.307G>A(p.Val103Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000531 in 1,209,678 control chromosomes in the GnomAD database, including 1 homozygotes. There are 187 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00055 (0 hom. 182 hem.)
• Consequence: MAGED1 NM_006986.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.29

Genes affected

MAGED1 (HGNC:6813): (MAGE family member D1) This gene is a member of the melanoma antigen gene (MAGE) family. Most of the genes of this family encode tumor specific antigens that are not expressed in normal adult tissues except testis. Although the protein encoded by this gene shares strong homology with members of the MAGE family, it is expressed in almost all normal adult tissues. This gene has been demonstrated to be involved in the p75 neurotrophin receptor mediated programmed cell death pathway. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01036182).
• BP6: Variant X-51895314-G-A is Benign according to our data. Variant chrX-51895314-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2350656.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGED1	NM_006986.4	c.307G>A	p.Val103Met	missense_variant	3/13	ENST00000326587.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGED1	ENST00000326587.12	c.307G>A	p.Val103Met	missense_variant	3/13	1	NM_006986.4	P2

Frequencies

GnomAD3 genomes AF: 0.000320 AC: 36 AN: 112391 Hom.: 1 Cov.: 23 AF XY: 0.000145 AC XY: 5 AN XY: 34547

Gnomad AFR AF: 0.000291

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: 0.000507

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000223 AC: 40 AN: 179714 Hom.: 0 AF XY: 0.000249 AC XY: 16 AN XY: 64328

Gnomad AFR exome AF: 0.000233

Gnomad AMR exome AF: 0.0000368

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000636

Gnomad NFE exome AF: 0.000425

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000552 AC: 606 AN: 1097233 Hom.: 0 Cov.: 32 AF XY: 0.000502 AC XY: 182 AN XY: 362619

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000285

Gnomad4 ASJ exome AF: 0.000103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000124

Gnomad4 NFE exome AF: 0.000697

Gnomad4 OTH exome AF: 0.000195

GnomAD4 genome AF: 0.000320 AC: 36 AN: 112445 Hom.: 1 Cov.: 23 AF XY: 0.000144 AC XY: 5 AN XY: 34611

Gnomad4 AFR AF: 0.000290

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: 0.000507

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000360 Hom.: 16

Bravo AF: 0.000242

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000296 AC: 36

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.58
Dann	Benign	0.64
DEOGEN2	Benign	0.10	T;T;T;.
FATHMM_MKL	Benign	0.026	N
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.26	N;N;N;N
REVEL	Benign	0.035
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.34	T;T;T;T
Polyphen		0.073	B;B;B;B
Vest4		0.053
MVP		0.21
MPC		0.077
ClinPred		0.011	T
GERP RS		2.8
Varity_R		0.039
gMVP		0.11

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: rs141080853; hg19: chrX-51638410; COSMIC: COSV58514327; COSMIC: COSV58514327;