chrX-149884716-C-A

Variant names:

• chrX-149884716-C-A
• rs1557370960
• NM_005364.5:c.444C>A

Variant summary

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

The NM_005364.5(MAGEA8):​c.444C>A​(p.Asn148Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000273 in 1,097,904 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: 23)
  • Exomes 𝑓: 0.0000027 (0 hom. 2 hem.)
• Consequence: MAGEA8 NM_005364.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.144
• Publications: 0 publications found

Genes affected

MAGEA8 (HGNC:6806): (MAGE family member A8) 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. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Oct 2009]

MAGEA8-AS1 (HGNC:45093): (MAGEA8 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08392626).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005364.5. 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
	MAGEA8	NM_005364.5	MANE Select	c.444C>A	p.Asn148Lys	missense	Exon 3 of 3	NP_005355.2
	MAGEA8	NM_001166400.2		c.444C>A	p.Asn148Lys	missense	Exon 4 of 4	NP_001159872.1	P43361
	MAGEA8	NM_001166401.2		c.444C>A	p.Asn148Lys	missense	Exon 3 of 3	NP_001159873.1	P43361

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGEA8	ENST00000286482.6	TSL:1 MANE Select	c.444C>A	p.Asn148Lys	missense	Exon 3 of 3	ENSP00000286482.1	P43361
	MAGEA8	ENST00000535454.5	TSL:3	c.444C>A	p.Asn148Lys	missense	Exon 4 of 4	ENSP00000438293.1	P43361
	MAGEA8	ENST00000542674.5	TSL:3	c.444C>A	p.Asn148Lys	missense	Exon 3 of 3	ENSP00000443776.1	P43361

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183264 AF XY: 0.0000148

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000273 AC: 3 AN: 1097904 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 2 AN XY: 363266

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35201

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54121

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00000356 AC: 3 AN: 841866

Other (OTH) AF: 0.00 AC: 0 AN: 46077

GnomAD4 genome Cov.: 23

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.95
CADD	Benign	3.3
DANN	Benign	0.92
DEOGEN2	Benign	0.0060	T
FATHMM_MKL	Benign	0.0021	N
LIST_S2	Benign	0.020	T
M_CAP	Benign	0.00093	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.48	N
PhyloP100		-0.14
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.037
Sift	Benign	0.55	T
Sift4G	Benign	0.34	T
Polyphen		0.075	B
Vest4		0.14
MutPred		0.52		Gain of methylation at N148 (P = 0.0071)
MVP		0.45
MPC		0.35
ClinPred		0.051	T
GERP RS		-0.21
Varity_R		0.11
gMVP		0.11
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: rs1557370960; hg19: chrX-149013490;