chrX-30251025-G-C

Variant names:

• chrX-30251025-G-C
• rs34171800
• NM_177404.3:c.532G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_177404.3(MAGEB1):​c.532G>C​(p.Val178Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,209,645 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V178I) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: MAGEB1 NM_177404.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.155
• Publications: 1 publications found

Genes affected

MAGEB1 (HGNC:6808): (MAGE family member B1) This gene is a member of the MAGEB gene family. The members of this family have their entire coding sequences located in the last exon, and the encoded proteins show 50 to 68% sequence identity to each other. The promoters and first exons of the MAGEB genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls. This gene is localized in the DSS (dosage-sensitive sex reversal) critical region, and expressed in testis and in a significant fraction of tumors of various histological types. This gene and other MAGEB members are clustered on chromosome Xp22-p21. Multiple alternatively spliced transcript variants encoding the same protein have been found for this gene, however, the full length nature of some variants has not been defined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2688374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEB1	NM_177404.3	c.532G>C	p.Val178Leu	missense_variant	Exon 2 of 2	ENST00000397548.4	NP_796379.1
MAGEB1	NM_002363.5	c.532G>C	p.Val178Leu	missense_variant	Exon 4 of 4		NP_002354.2
MAGEB1	NM_177415.3	c.532G>C	p.Val178Leu	missense_variant	Exon 3 of 3		NP_803134.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEB1	ENST00000397548.4	c.532G>C	p.Val178Leu	missense_variant	Exon 2 of 2	1	NM_177404.3	ENSP00000380681.2
MAGEB1	ENST00000378981.8	c.532G>C	p.Val178Leu	missense_variant	Exon 4 of 4	1		ENSP00000368264.3
MAGEB1	ENST00000397550.6	c.532G>C	p.Val178Leu	missense_variant	Exon 3 of 3	1		ENSP00000380683.1

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111925 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000939

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 AF: 9.11e-7 AC: 1 AN: 1097720 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363086

African (AFR) AF: 0.00 AC: 0 AN: 26401

American (AMR) AF: 0.0000284 AC: 1 AN: 35163

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 53964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841869

Other (OTH) AF: 0.00 AC: 0 AN: 46089

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111925 Hom.: 0 Cov.: 24 AF XY: 0.0000293 AC XY: 1 AN XY: 34137

African (AFR) AF: 0.00 AC: 0 AN: 30761

American (AMR) AF: 0.0000939 AC: 1 AN: 10646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3557

South Asian (SAS) AF: 0.00 AC: 0 AN: 2614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53167

Other (OTH) AF: 0.00 AC: 0 AN: 1506

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.043	T;T;T
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.38	.;T;.
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;M;M
PhyloP100		-0.15
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.4	N;N;N
REVEL	Benign	0.070
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.035	D;D;D
Polyphen		0.95	P;P;P
Vest4		0.069
MutPred		0.68		Gain of disorder (P = 0.1352);Gain of disorder (P = 0.1352);Gain of disorder (P = 0.1352);
MVP		0.33
MPC		0.14
ClinPred		0.36	T
GERP RS		0.21
Varity_R		0.27
gMVP		0.33
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs34171800; hg19: chrX-30269142;