Genetic Variant MAMLD1:p.Met74Ile (chrX-150469795-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.04

Publications

0 publications found

Variant links:

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

MAMLD1 links:

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ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAMLD1	NM_005491.5	MANE Select	c.222G>A	p.Met74Ile	missense	Exon 4 of 8	NP_005482.2	Q13495-1
MAMLD1	NM_001400512.1		c.222G>A	p.Met74Ile	missense	Exon 4 of 6	NP_001387441.1	A0A804HKM8
MAMLD1	NM_001177465.3		c.147G>A	p.Met49Ile	missense	Exon 3 of 5	NP_001170936.1	Q13495-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAMLD1	ENST00000370401.7	TSL:5 MANE Select	c.222G>A	p.Met74Ile	missense	Exon 4 of 8	ENSP00000359428.2	Q13495-1
MAMLD1	ENST00000426613.5	TSL:1	c.147G>A	p.Met49Ile	missense	Exon 4 of 8	ENSP00000397438.2	Q13495-4
MAMLD1	ENST00000682016.1		c.222G>A	p.Met74Ile	missense	Exon 5 of 7	ENSP00000507991.1	A0A804HKM8

Frequencies

GnomAD3 genomes

AF:

0.0000271

AC:

AN:

110829

Hom.:

Cov.:

show subpopulations

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.:

GnomAD4 genome

AF:

0.0000271

AC:

AN:

110829

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33043

show subpopulations

African (AFR)

AF:

0.0000988

AC:

AN:

30368

American (AMR)

AF:

0.00

AC:

AN:

10411

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2635

East Asian (EAS)

AF:

0.00

AC:

AN:

3529

South Asian (SAS)

AF:

0.00

AC:

AN:

2619

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52956

Other (OTH)

AF:

0.00

AC:

AN:

1486

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.066

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.85

M_CAP

Pathogenic

0.54

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.1

PhyloP100

5.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.8

REVEL

Benign

0.24

Sift

Benign

0.075

Sift4G

Benign

0.27

Polyphen

0.96

Vest4

0.35

MutPred

0.53

Loss of disorder (P = 0.0578)

MVP

0.56

MPC

0.56

ClinPred

0.90

GERP RS

4.3

Varity_R

0.45

gMVP

0.15

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over