X-150469795-G-C

Variant names:

• chrX-150469795-G-C
• rs1396185489
• NM_005491.5:c.222G>C

Variant summary

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

The NM_005491.5(MAMLD1):​c.222G>C​(p.Met74Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000902 in 110,829 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 22)
• Consequence: MAMLD1 NM_005491.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• 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 2 ACMG points.

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

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.222G>C	p.Met74Ile	missense	Exon 4 of 8	NP_005482.2	Q13495-1
	MAMLD1	NM_001400512.1		c.222G>C	p.Met74Ile	missense	Exon 4 of 6	NP_001387441.1	A0A804HKM8
	MAMLD1	NM_001177465.3		c.147G>C	p.Met49Ile	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.222G>C	p.Met74Ile	missense	Exon 4 of 8	ENSP00000359428.2	Q13495-1
	MAMLD1	ENST00000426613.5	TSL:1	c.147G>C	p.Met49Ile	missense	Exon 4 of 8	ENSP00000397438.2	Q13495-4
	MAMLD1	ENST00000682016.1		c.222G>C	p.Met74Ile	missense	Exon 5 of 7	ENSP00000507991.1	A0A804HKM8

Frequencies

GnomAD3 genomes AF: 0.00000902 AC: 1 AN: 110829 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000329

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: 0.00000902 AC: 1 AN: 110829 Hom.: 0 Cov.: 22 AF XY: 0.0000303 AC XY: 1 AN XY: 33043

African (AFR) AF: 0.0000329 AC: 1 AN: 30368

American (AMR) AF: 0.00 AC: 0 AN: 10411

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3529

South Asian (SAS) AF: 0.00 AC: 0 AN: 2619

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52956

Other (OTH) AF: 0.00 AC: 0 AN: 1486

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.24
Sift	Benign	0.075	T
Sift4G	Benign	0.27	T
Polyphen		0.96	D
Vest4		0.35
MutPred		0.53		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
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

dbSNP: rs1396185489; hg19: chrX-149638067;