NM_021048.5:c.401T>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_021048.5(MAGEA10):​c.401T>C​(p.Ile134Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00017 in 1,207,961 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 67 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.00017 (0 hom. 65 hem.)
• Consequence: MAGEA10 NM_021048.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.203
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.076803535).
• BP6: Variant X-152135220-A-G is Benign according to our data. Variant chrX-152135220-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2460568.
• BS2: High Hemizygotes in GnomAd4 at 2 gene

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.401T>C	p.Ile134Thr	missense	Exon 4 of 4	NP_066386.3	P43363
	MAGEA10	NM_001011543.3		c.401T>C	p.Ile134Thr	missense	Exon 5 of 5	NP_001011543.3	P43363
	MAGEA10	NM_001251828.2		c.401T>C	p.Ile134Thr	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.401T>C	p.Ile134Thr	missense	Exon 4 of 4	ENSP00000359347.4	P43363
	MAGEA10	ENST00000244096.7	TSL:2	c.401T>C	p.Ile134Thr	missense	Exon 5 of 5	ENSP00000244096.3	P43363
	MAGEA10	ENST00000444834.6	TSL:3	c.401T>C	p.Ile134Thr	missense	Exon 5 of 5	ENSP00000406161.2	C9J958

Frequencies

GnomAD3 genomes AF: 0.000134 AC: 15 AN: 111627 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000947

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000326

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000133 AC: 24 AN: 181113 AF XY: 0.0000305

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000569

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000173 AC: 190 AN: 1096334 Hom.: 0 Cov.: 32 AF XY: 0.000180 AC XY: 65 AN XY: 361840

African (AFR) AF: 0.0000379 AC: 1 AN: 26355

American (AMR) AF: 0.00 AC: 0 AN: 35102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19275

East Asian (EAS) AF: 0.00 AC: 0 AN: 30175

South Asian (SAS) AF: 0.00 AC: 0 AN: 53836

European-Finnish (FIN) AF: 0.000494 AC: 20 AN: 40463

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.000197 AC: 166 AN: 841009

Other (OTH) AF: 0.0000652 AC: 3 AN: 45996

GnomAD4 genome AF: 0.000134 AC: 15 AN: 111627 Hom.: 0 Cov.: 22 AF XY: 0.0000591 AC XY: 2 AN XY: 33817

African (AFR) AF: 0.0000652 AC: 2 AN: 30654

American (AMR) AF: 0.0000947 AC: 1 AN: 10561

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00 AC: 0 AN: 3515

South Asian (SAS) AF: 0.00 AC: 0 AN: 2591

European-Finnish (FIN) AF: 0.000326 AC: 2 AN: 6132

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

European-Non Finnish (NFE) AF: 0.000188 AC: 10 AN: 53104

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.000324 Hom.: 1

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.0000824 AC: 10

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.72
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.12	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		0.20
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.054
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.94	P
Vest4		0.38
MVP		0.35
MPC		0.48
ClinPred		0.15	T
GERP RS		1.4
Varity_R		0.62
gMVP		0.25
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: rs377180452; hg19: chrX-151303692;