Genetic Variant NM_005491.5:c.406A>G (chrX-150469979-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005491.5(MAMLD1):c.406A>G(p.Met136Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,239 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M136L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

MAMLD1
NM_005491.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.652

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14887863).

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.406A>G	p.Met136Val	missense	Exon 4 of 8	NP_005482.2	Q13495-1
MAMLD1	NM_001400512.1		c.406A>G	p.Met136Val	missense	Exon 4 of 6	NP_001387441.1	A0A804HKM8
MAMLD1	NM_001177465.3		c.331A>G	p.Met111Val	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.406A>G	p.Met136Val	missense	Exon 4 of 8	ENSP00000359428.2	Q13495-1
MAMLD1	ENST00000426613.5	TSL:1	c.331A>G	p.Met111Val	missense	Exon 4 of 8	ENSP00000397438.2	Q13495-4
MAMLD1	ENST00000682016.1		c.406A>G	p.Met136Val	missense	Exon 5 of 7	ENSP00000507991.1	A0A804HKM8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1098239

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363593

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54147

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

842132

Other (OTH)

AF:

0.00

AC:

AN:

46095

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.60

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.060

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.75

M_CAP

Benign

0.032

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

0.65

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.5

REVEL

Benign

0.047

Sift

Benign

0.089

Sift4G

Benign

0.46

Polyphen

0.0010

Vest4

0.12

MutPred

0.21

Loss of disorder (P = 0.0724)

MVP

0.17

MPC

0.21

ClinPred

0.097

GERP RS

-1.4

Varity_R

0.25

gMVP

0.27

Mutation Taster

=92/8

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