X-150469795-G-A

Position:

• chrX-150469795-G-A

Variant summary

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

The NM_005491.5(MAMLD1):​c.222G>A​(p.Met74Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000271 in 110,829 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 22)
• Consequence: MAMLD1 NM_005491.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

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.222G>A	p.Met74Ile	missense_variant	4/8	ENST00000370401.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAMLD1	ENST00000370401.7	c.222G>A	p.Met74Ile	missense_variant	4/8	5	NM_005491.5	A2

Frequencies

GnomAD3 genomes AF: 0.0000271 AC: 3 AN: 110829 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33043

Gnomad AFR AF: 0.0000988

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.0000271 AC: 3 AN: 110829 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33043

Gnomad4 AFR AF: 0.0000988

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

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

Jun 17, 2024

The c.222G>A (p.M74I) alteration is located in exon 3 (coding exon 3) of the MAMLD1 gene. This alteration results from a G to A substitution at nucleotide position 222, causing the methionine (M) at amino acid position 74 to be replaced by an isoleucine (I). 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	Uncertain	0.54
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.066	T;.;T;.;T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	.;T;D;T;T
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.1	M;.;.;.;M
MutationTaster	Benign	0.60	N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N;N;D;N;N
REVEL	Benign	0.24
Sift	Benign	0.075	T;D;D;T;T
Sift4G	Benign	0.27	T;T;D;T;T
Polyphen		0.96	D;P;.;D;D
Vest4		0.35
MutPred		0.53		Loss of disorder (P = 0.0578);.;Loss of disorder (P = 0.0578);.;Loss of disorder (P = 0.0578);
MVP		0.56
MPC		0.56
ClinPred		0.90	D
GERP RS		4.3
Varity_R		0.45
gMVP		0.15

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: rs1396185489; hg19: chrX-149638067;