X-150512252-A-T

Variant names:

• chrX-150512252-A-T
• NM_005491.5:c.*293A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001400512.1(MAMLD1):​c.2251A>T​(p.Arg751*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MAMLD1 NM_001400512.1 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63
• Publications: 0 publications found

Genes affected

MAMLD1 (HGNC:2568): (mastermind like domain containing 1) This gene encodes a mastermind-like domain containing protein. This protein may function as a transcriptional co-activator. Mutations in this gene are the cause of X-linked hypospadias type 2. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

MAMLD1 Gene-Disease associations (from GenCC):

• hypospadias 2, X-linked

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.267 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001400512.1. 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
	MAMLD1	NM_005491.5	MANE Select	c.*293A>T		3_prime_UTR	Exon 8 of 8	NP_005482.2	Q13495-1
	MAMLD1	NM_001400512.1		c.2251A>T	p.Arg751*	stop_gained	Exon 6 of 6	NP_001387441.1	A0A804HKM8
	MAMLD1	NM_001177465.3		c.2176A>T	p.Arg726*	stop_gained	Exon 5 of 5	NP_001170936.1	Q13495-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAMLD1	ENST00000370401.7	TSL:5 MANE Select	c.*293A>T		3_prime_UTR	Exon 8 of 8	ENSP00000359428.2	Q13495-1
	MAMLD1	ENST00000426613.5	TSL:1	c.*293A>T		3_prime_UTR	Exon 8 of 8	ENSP00000397438.2	Q13495-4
	MAMLD1	ENST00000464149.1	TSL:1	n.971A>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	4.7
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.87	D
PhyloP100		2.6
Mutation Taster		=49/151	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-149680522;