NM_005491.5:c.2176C>T

Variant names:

• chrX-150503409-C-T
• rs121909495
• NM_005491.5:c.2176C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005491.5(MAMLD1):​c.2176C>T​(p.Arg726*) 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. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: MAMLD1 NM_005491.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.231
• Publications: 5 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-150503409-C-T is Pathogenic according to our data. Variant chrX-150503409-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11613.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAMLD1	NM_005491.5	c.2176C>T	p.Arg726*	stop_gained	Exon 6 of 8	ENST00000370401.7	NP_005482.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAMLD1	ENST00000370401.7	c.2176C>T	p.Arg726*	stop_gained	Exon 6 of 8	5	NM_005491.5	ENSP00000359428.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

Alfa AF: 0.000103 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

46,XY ovotesticular disorder of sex development Pathogenic:1

-

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MAMLD1 p.Arg726* variant has previously been reported as pathogenic in a 46,XY individual with hypospadias (PMID: 17086185). The clinical features reported for that patient included penoscrotal hypospadias with chordee, microphallus, bifid scrotum and retractile testes. Primary hypogonadism and testicular microlithiasis were reported in a subsequent study, following examination of the patient at 9 years of age (PMID: 27383042). The variant was maternally inherited (PMID: 17086185). The MAMLD1 p.Arg726* variant replaces the arginine at position 726 with a premature termination codon. This variant has been experimentally demonstrated to undergo nonsense mediated mRNA decay and cause a loss of protein function (PMID: 18162467). This variant is absent from large population cohorts (Genome Aggregation Database v2.1; 0 of ~183,000 alleles). -

Hypospadias 2, X-linked Pathogenic:1

Dec 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.38	N
PhyloP100		0.23
Vest4		0.83
GERP RS		1.6
Mutation Taster		=11/189	disease causing (ClinVar)

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: rs121909495; hg19: chrX-149671679;