rs121909495
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_005491.5(MAMLD1):c.2176C>T(p.Arg726Ter) 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
NM_005491.5 stop_gained
Scores
1
1
3
Clinical Significance
Conservation
PhyloP100: 0.231
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 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 id is 11613.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MAMLD1 | NM_005491.5 | c.2176C>T | p.Arg726Ter | stop_gained | 6/8 | ENST00000370401.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MAMLD1 | ENST00000370401.7 | c.2176C>T | p.Arg726Ter | stop_gained | 6/8 | 5 | NM_005491.5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 24
GnomAD3 genomes
?
Cov.:
24
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 24
GnomAD4 genome
?
Cov.:
24
Alfa
AF:
Hom.:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
46,XY ovotesticular disorder of sex development Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | - | 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
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2006 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A;A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at