X-149715748-C-T

Position:

• chrX-149715748-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000355220.6(MAGEA11):​c.267-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0008 in 1,200,313 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 342 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., 30 hem., cov: 22)
  • Exomes 𝑓: 0.00080 (0 hom. 312 hem.)
• Consequence: MAGEA11 ENST00000355220.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000007203
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0380

Genes affected

MAGEA11 (HGNC:6798): (MAGE family member A11) 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. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-149715748-C-T is Benign according to our data. Variant chrX-149715748-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3049970.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Hemizygotes in GnomAd4 at 30 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAGEA11	NM_005366.5	c.267-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000355220.6	NP_005357.2
MAGEA11	NM_001011544.2	c.180-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001011544.1
MAGEA11	XM_011531164.3	c.243-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011529466.1
MAGEA11	XM_047442106.1	c.267-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_047298062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAGEA11	ENST00000355220.6	c.267-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005366.5	ENSP00000347358	P2
MAGEA11	ENST00000333104.8	c.180-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000328177	A2
MAGEA11	ENST00000412632.6	c.180-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000391496
MAGEA11	ENST00000518694.1	n.1857-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 85 AN: 111613 Hom.: 0 Cov.: 22 AF XY: 0.000888 AC XY: 30 AN XY: 33791

Gnomad AFR AF: 0.0000979

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000947

Gnomad ASJ AF: 0.00340

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00189

Gnomad FIN AF: 0.00248

Gnomad MID AF: 0.0171

Gnomad NFE AF: 0.000885

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00118 AC: 202 AN: 171703 Hom.: 0 AF XY: 0.00144 AC XY: 83 AN XY: 57725

Gnomad AFR exome AF: 0.000154

Gnomad AMR exome AF: 0.000420

Gnomad ASJ exome AF: 0.00252

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00194

Gnomad FIN exome AF: 0.00345

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00215

GnomAD4 exome AF: 0.000804 AC: 875 AN: 1088646 Hom.: 0 Cov.: 32 AF XY: 0.000877 AC XY: 312 AN XY: 355646

Gnomad4 AFR exome AF: 0.0000382

Gnomad4 AMR exome AF: 0.000407

Gnomad4 ASJ exome AF: 0.00150

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00200

Gnomad4 FIN exome AF: 0.00269

Gnomad4 NFE exome AF: 0.000648

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.000761 AC: 85 AN: 111667 Hom.: 0 Cov.: 22 AF XY: 0.000886 AC XY: 30 AN XY: 33855

Gnomad4 AFR AF: 0.0000977

Gnomad4 AMR AF: 0.0000946

Gnomad4 ASJ AF: 0.00340

Gnomad4 EAS AF: 0.000282

Gnomad4 SAS AF: 0.00190

Gnomad4 FIN AF: 0.00248

Gnomad4 NFE AF: 0.000885

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00130 Hom.: 7

Bravo AF: 0.000635

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

MAGEA11-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.9
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000072
dbscSNV1_RF	Benign	0.0
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: rs200012022; hg19: chrX-148797408;