NM_177404.3:c.515G>A

Variant names:

• chrX-30251008-G-A
• rs1284673276
• NM_177404.3:c.515G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_177404.3(MAGEB1):​c.515G>A​(p.Gly172Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,900 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000036 (0 hom. 2 hem.)
• Consequence: MAGEB1 NM_177404.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.371
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23706722).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEB1	NM_177404.3	c.515G>A	p.Gly172Asp	missense_variant	Exon 2 of 2	ENST00000397548.4	NP_796379.1
MAGEB1	NM_002363.5	c.515G>A	p.Gly172Asp	missense_variant	Exon 4 of 4		NP_002354.2
MAGEB1	NM_177415.3	c.515G>A	p.Gly172Asp	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.515G>A	p.Gly172Asp	missense_variant	Exon 2 of 2	1	NM_177404.3	ENSP00000380681.2
MAGEB1	ENST00000378981.8	c.515G>A	p.Gly172Asp	missense_variant	Exon 4 of 4	1		ENSP00000368264.3
MAGEB1	ENST00000397550.6	c.515G>A	p.Gly172Asp	missense_variant	Exon 3 of 3	1		ENSP00000380683.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097900 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 363258

African (AFR) AF: 0.0000379 AC: 1 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35183

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 53998

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40522

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

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 841987

Other (OTH) AF: 0.00 AC: 0 AN: 46086

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.515G>A (p.G172D) alteration is located in exon 4 (coding exon 1) of the MAGEB1 gene. This alteration results from a G to A substitution at nucleotide position 515, causing the glycine (G) at amino acid position 172 to be replaced by an aspartic acid (D). 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	0.16
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.15
DEOGEN2	Benign	0.015	T;T;T
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.0052	.;T;.
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;M
PhyloP100		0.37
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.3	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.65	T;T;T
Polyphen		0.98	D;D;D
Vest4		0.23
MutPred		0.32		Gain of phosphorylation at Y175 (P = 0.091);Gain of phosphorylation at Y175 (P = 0.091);Gain of phosphorylation at Y175 (P = 0.091);
MVP		0.42
MPC		0.19
ClinPred		0.45	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.093
gMVP		0.21
Mutation Taster		=99/1	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: rs1284673276; hg19: chrX-30269125;