X-54809901-T-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_177433.3(MAGED2):c.225T>C(p.Ala75=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000762 in 1,191,064 control chromosomes in the GnomAD database, including 5 homozygotes. There are 239 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (4 hom., 115 hem., cov: 22)
  • Exomes 𝑓: 0.00042 (1 hom. 124 hem.)
• Consequence: MAGED2 NM_177433.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.189

Genes affected

MAGED2 (HGNC:16353): (MAGE family member D2) This gene is a member of the MAGED gene family. The MAGED genes are clustered on chromosome Xp11. This gene is located in Xp11.2, a hot spot for X-linked intellectual disability (XLID). Mutations in this gene cause a form of transient antenatal Bartter's syndrome. This gene may also be involved in several types of cancer, including breast cancer and melanoma. The protein encoded by this gene is progressively recruited from the cytoplasm to the nucleoplasm during the interphase and after nucleolar stress and is thus thought to play a role in cell cycle regulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant X-54809901-T-C is Benign according to our data. Variant chrX-54809901-T-C is described in ClinVar as [Benign]. Clinvar id is 721675.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.189 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAGED2	NM_177433.3	c.225T>C	p.Ala75=	synonymous_variant	3/13	ENST00000375068.6
MAGED2	NM_014599.6	c.225T>C	p.Ala75=	synonymous_variant	3/13
MAGED2	NM_201222.3	c.225T>C	p.Ala75=	synonymous_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAGED2	ENST00000375068.6	c.225T>C	p.Ala75=	synonymous_variant	3/13	1	NM_177433.3	P1

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 453 AN: 110165 Hom.: 4 Cov.: 22 AF XY: 0.00351 AC XY: 114 AN XY: 32449

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000402

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000152

Gnomad OTH AF: 0.00741

GnomAD3 exomes AF: 0.00116 AC: 172 AN: 148526 Hom.: 2 AF XY: 0.000799 AC XY: 36 AN XY: 45056

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.000930

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000639

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.000416 AC: 450 AN: 1080847 Hom.: 1 Cov.: 31 AF XY: 0.000353 AC XY: 124 AN XY: 351453

Gnomad4 AFR exome AF: 0.0129

Gnomad4 AMR exome AF: 0.000865

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000384

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000372

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.00415 AC: 457 AN: 110217 Hom.: 4 Cov.: 22 AF XY: 0.00354 AC XY: 115 AN XY: 32511

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.00210

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000152

Gnomad4 OTH AF: 0.00732

Alfa AF: 0.00208 Hom.: 9

Bravo AF: 0.00435

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	10
Dann	Benign	0.79

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: rs144346983; hg19: chrX-54836334;