X-152135601-C-G

Variant names:

• chrX-152135601-C-G
• rs145553450
• NM_021048.5:c.20G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021048.5(MAGEA10):​c.20G>C​(p.Arg7Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000977 in 1,023,233 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 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. R7H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.8e-7 (0 hom. 0 hem.)
• Consequence: MAGEA10 NM_021048.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.489
• Publications: 0 publications found

Genes affected

MAGEA10 (HGNC:6797): (MAGE family member A10) This gene is a member of the MAGEA gene family. The members of this family encode proteins with 50 to 80% sequence identity to each other. The promoters and first exons of the MAGEA genes show considerable variability, suggesting that the existence of this gene family enables the same function to be expressed under different transcriptional controls. The MAGEA genes are clustered at chromosomal location Xq28. They have been implicated in some hereditary disorders, such as dyskeratosis congenita. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream melanoma antigen family A, 5 (MAGEA5) gene.[provided by RefSeq, Oct 2011]

LOC100533997 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15448216).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021048.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGEA10	NM_021048.5	MANE Select	c.20G>C	p.Arg7Pro	missense	Exon 4 of 4	NP_066386.3	P43363
	MAGEA10	NM_001011543.3		c.20G>C	p.Arg7Pro	missense	Exon 5 of 5	NP_001011543.3	P43363
	MAGEA10	NM_001251828.2		c.20G>C	p.Arg7Pro	missense	Exon 5 of 5	NP_001238757.2	P43363

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGEA10	ENST00000370323.9	TSL:1 MANE Select	c.20G>C	p.Arg7Pro	missense	Exon 4 of 4	ENSP00000359347.4	P43363
	MAGEA10	ENST00000244096.7	TSL:2	c.20G>C	p.Arg7Pro	missense	Exon 5 of 5	ENSP00000244096.3	P43363
	MAGEA10	ENST00000444834.6	TSL:3	c.20G>C	p.Arg7Pro	missense	Exon 5 of 5	ENSP00000406161.2	C9J958

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.77e-7 AC: 1 AN: 1023233 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 325165

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23699

American (AMR) AF: 0.00 AC: 0 AN: 23103

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14667

East Asian (EAS) AF: 0.00 AC: 0 AN: 29548

South Asian (SAS) AF: 0.00 AC: 0 AN: 41544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37621

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3783

European-Non Finnish (NFE) AF: 0.00000124 AC: 1 AN: 806489

Other (OTH) AF: 0.00 AC: 0 AN: 42779

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.79
DEOGEN2	Benign	0.015	T
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.49
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.12
Sift	Benign	0.12	T
Sift4G	Benign	0.083	T
Polyphen		0.99	D
Vest4		0.40
MutPred		0.37		Loss of MoRF binding (P = 2e-04)
MVP		0.44
MPC		0.53
ClinPred		0.83	D
GERP RS		0.55
Varity_R		0.37
gMVP		0.18
Mutation Taster		=98/2	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: rs145553450; hg19: chrX-151304073;