chrX-150470082-C-A

Variant names:

• chrX-150470082-C-A
• NM_005491.5:c.509C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005491.5(MAMLD1):​c.509C>A​(p.Pro170Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P170L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MAMLD1 NM_005491.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24470437).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005491.5. 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.509C>A	p.Pro170Gln	missense	Exon 4 of 8	NP_005482.2	Q13495-1
	MAMLD1	NM_001400512.1		c.509C>A	p.Pro170Gln	missense	Exon 4 of 6	NP_001387441.1	A0A804HKM8
	MAMLD1	NM_001177465.3		c.434C>A	p.Pro145Gln	missense	Exon 3 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.509C>A	p.Pro170Gln	missense	Exon 4 of 8	ENSP00000359428.2	Q13495-1
	MAMLD1	ENST00000426613.5	TSL:1	c.434C>A	p.Pro145Gln	missense	Exon 4 of 8	ENSP00000397438.2	Q13495-4
	MAMLD1	ENST00000682016.1		c.509C>A	p.Pro170Gln	missense	Exon 5 of 7	ENSP00000507991.1	A0A804HKM8

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.029	T
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.094
Sift	Benign	0.36	T
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.14
MutPred		0.24		Loss of loop (P = 0.0288)
MVP		0.63
MPC		0.20
ClinPred		0.11	T
GERP RS		2.3
Varity_R		0.078
gMVP		0.52
Mutation Taster		=99/1	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

hg19: chrX-149638354;