Variant X-150469843-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_005491.5(MAMLD1):c.270T>A(p.Asp90Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,209,887 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000018 ( 0 hom. 4 hem. )

Consequence

MAMLD1
NM_005491.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.199

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAMLD1	NM_005491.5 linkuse as main transcript	c.270T>A	p.Asp90Glu	missense_variant	4/8	ENST00000370401.7	NP_005482.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAMLD1	ENST00000370401.7 linkuse as main transcript	c.270T>A	p.Asp90Glu	missense_variant	4/8	5	NM_005491.5	ENSP00000359428	A2	Q13495-1

Frequencies

GnomAD3 genomes

AF:

0.00000893

AC:

AN:

111992

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34156

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000546

AC:

AN:

183104

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67572

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000182

AC:

AN:

1097895

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

363287

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000226

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000893

AC:

AN:

111992

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34156

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 21, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with MAMLD1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.001%). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 90 of the MAMLD1 protein (p.Asp90Glu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

T;.;T;.;T

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.88

.;D;T;D;D

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.74

D;D;D;D;D

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.9

M;.;.;.;M

MutationTaster

Benign

0.87

D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.0

N;N;D;N;N

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Benign

0.26

T;T;D;T;T

Polyphen

1.0

D;D;.;D;D

Vest4

0.63

MutPred

0.77

Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);

MVP

0.54

MPC

0.69

ClinPred

0.91

GERP RS

-1.6

Varity_R

0.65

gMVP

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over