X-150470034-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005491.5(MAMLD1):c.461G>T(p.Gly154Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MAMLD1 NM_005491.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.391

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAMLD1	NM_005491.5	c.461G>T	p.Gly154Val	missense_variant	4/8	ENST00000370401.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAMLD1	ENST00000370401.7	c.461G>T	p.Gly154Val	missense_variant	4/8	5	NM_005491.5	A2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 2023

The c.461G>T (p.G154V) alteration is located in exon 3 (coding exon 3) of the MAMLD1 gene. This alteration results from a G to T substitution at nucleotide position 461, causing the glycine (G) at amino acid position 154 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	16
Dann	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;.;T
FATHMM_MKL	Benign	0.061	N
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.8	M;.;.;M
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Benign	0.29
Sift	Benign	0.048	D;D;D;D
Sift4G	Benign	0.32	T;T;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.27
MutPred		0.64		Gain of sheet (P = 0.0266);.;.;Gain of sheet (P = 0.0266);
MVP		0.82
MPC		0.76
ClinPred		0.71	D
GERP RS		2.6
Varity_R		0.24
gMVP		0.53

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: rs781965917; hg19: chrX-149638306;