X-152135220-A-T

Variant names:

• chrX-152135220-A-T
• rs377180452
• NM_021048.5:c.401T>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021048.5(MAGEA10):​c.401T>A​(p.Ile134Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. I134T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: MAGEA10 NM_021048.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.203

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.281413).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAGEA10	NM_021048.5	c.401T>A	p.Ile134Lys	missense_variant	Exon 4 of 4	ENST00000370323.9	NP_066386.3
MAGEA10	NM_001011543.3	c.401T>A	p.Ile134Lys	missense_variant	Exon 5 of 5		NP_001011543.3
MAGEA10	NM_001251828.2	c.401T>A	p.Ile134Lys	missense_variant	Exon 5 of 5		NP_001238757.2
LOC100533997	NM_001204811.3	c.-278+3255T>A		intron_variant	Intron 1 of 3		NP_001191740.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAGEA10	ENST00000370323.9	c.401T>A	p.Ile134Lys	missense_variant	Exon 4 of 4	1	NM_021048.5	ENSP00000359347.4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000552 AC: 1 AN: 181113 Hom.: 0 AF XY: 0.0000152 AC XY: 1 AN XY: 65665

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.12e-7 AC: 1 AN: 1096334 Hom.: 0 Cov.: 32 AF XY: 0.00000276 AC XY: 1 AN XY: 361840

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.76
DEOGEN2	Benign	0.16	T;T;T;T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.11	.;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M;.;.
PrimateAI	Uncertain	0.48	T
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Benign	0.13
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;.;.
Polyphen		0.61	P;P;.;.
Vest4		0.58
MutPred		0.65		Gain of ubiquitination at I134 (P = 0.0048);Gain of ubiquitination at I134 (P = 0.0048);Gain of ubiquitination at I134 (P = 0.0048);Gain of ubiquitination at I134 (P = 0.0048);
MVP		0.22
MPC		0.39
ClinPred		0.31	T
GERP RS		1.4
Varity_R		0.61
gMVP		0.62

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: rs377180452; hg19: chrX-151303692;