rs768575994

Variant names:

• chrX-151924100-C-T
• rs768575994
• NM_001011548.1:c.436C>T

Variant summary

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

The NM_001011548.1(MAGEA4):​c.436C>T​(p.Arg146Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,210,726 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 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: 𝑓 0.000036 (0 hom., 2 hem., cov: 24)
  • Exomes 𝑓: 0.0000091 (0 hom. 2 hem.)
• Consequence: MAGEA4 NM_001011548.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.357
• Publications: 0 publications found

Genes affected

MAGEA4 (HGNC:6802): (MAGE family member A4) 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. Several variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.117432386).
• BS2: High Hemizygotes in GnomAd4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001011548.1. 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
	MAGEA4	NM_001011548.1	MANE Select	c.436C>T	p.Arg146Cys	missense	Exon 3 of 3	NP_001011548.1	P43358
	MAGEA4	NM_001011549.1		c.436C>T	p.Arg146Cys	missense	Exon 3 of 3	NP_001011549.1	P43358
	MAGEA4	NM_001011550.1		c.436C>T	p.Arg146Cys	missense	Exon 3 of 3	NP_001011550.1	P43358

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAGEA4	ENST00000276344.6	TSL:2 MANE Select	c.436C>T	p.Arg146Cys	missense	Exon 3 of 3	ENSP00000276344.2	P43358
	MAGEA4	ENST00000360243.6	TSL:1	c.436C>T	p.Arg146Cys	missense	Exon 3 of 3	ENSP00000353379.2	P43358
	MAGEA4	ENST00000370335.5	TSL:1	c.436C>T	p.Arg146Cys	missense	Exon 3 of 3	ENSP00000359360.1	P43358

Frequencies

GnomAD3 genomes AF: 0.0000355 AC: 4 AN: 112531 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000563

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 183448 AF XY: 0.00

Gnomad AFR exome AF: 0.0000760

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: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000911 AC: 10 AN: 1098195 Hom.: 0 Cov.: 37 AF XY: 0.00000550 AC XY: 2 AN XY: 363561

African (AFR) AF: 0.0000758 AC: 2 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40481

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

European-Non Finnish (NFE) AF: 0.00000950 AC: 8 AN: 842134

Other (OTH) AF: 0.00 AC: 0 AN: 46096

GnomAD4 genome AF: 0.0000355 AC: 4 AN: 112531 Hom.: 0 Cov.: 24 AF XY: 0.0000577 AC XY: 2 AN XY: 34681

African (AFR) AF: 0.0000323 AC: 1 AN: 30994

American (AMR) AF: 0.00 AC: 0 AN: 10680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00 AC: 0 AN: 2683

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6213

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

European-Non Finnish (NFE) AF: 0.0000563 AC: 3 AN: 53287

Other (OTH) AF: 0.00 AC: 0 AN: 1534

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.00000824 AC: 1

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	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	T
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.79	N
PhyloP100		-0.36
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.089
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.25
MutPred		0.51		Loss of MoRF binding (P = 0.0011)
MVP		0.10
MPC		0.0078
ClinPred		0.22	T
GERP RS		-4.3
Varity_R		0.34
gMVP		0.18
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: rs768575994; hg19: chrX-151092572;