NM_005491.5:c.394G>C

Variant names:

• chrX-150469967-G-C
• rs1135402752
• NM_005491.5:c.394G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005491.5(MAMLD1):​c.394G>C​(p.Glu132Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MAMLD1 NM_005491.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.61
• 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAMLD1	NM_005491.5	c.394G>C	p.Glu132Gln	missense_variant	Exon 4 of 8	ENST00000370401.7	NP_005482.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAMLD1	ENST00000370401.7	c.394G>C	p.Glu132Gln	missense_variant	Exon 4 of 8	5	NM_005491.5	ENSP00000359428.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;T;.;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.61	D;D;D;D;D
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Uncertain	2.7	M;.;.;.;M
PhyloP100		7.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.7	N;N;D;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Uncertain	0.024	D;D;D;D;D
Polyphen		0.96	D;D;.;D;D
Vest4		0.48
MutPred		0.55		Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);
MVP		0.71
MPC		0.70
ClinPred		0.91	D
GERP RS		5.4
Varity_R		0.26
gMVP		0.46
Mutation Taster		=79/21	polymorphism

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: rs1135402752; hg19: chrX-149638239;