rs62641609

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005491.5(MAMLD1):c.1041C>A(p.His347Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,209,902 control chromosomes in the GnomAD database, including 99 homozygotes. There are 1,103 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 51 hom., 521 hem., cov: 23)

Exomes 𝑓: 0.0020 ( 48 hom. 582 hem. )

Consequence

MAMLD1
NM_005491.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.18

Publications

6 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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

MAMLD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028254688).

BP6

Variant X-150470614-C-A is Benign according to our data. Variant chrX-150470614-C-A is described in ClinVar as Benign. ClinVar VariationId is 712305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAMLD1	NM_005491.5 link	c.1041C>A	p.His347Gln	missense_variant	Exon 4 of 8	ENST00000370401.7	NP_005482.2	Q13495-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAMLD1	ENST00000370401.7 link	c.1041C>A	p.His347Gln	missense_variant	Exon 4 of 8	5	NM_005491.5	ENSP00000359428.2		Q13495-1

Frequencies

GnomAD3 genomes

AF:

0.0179

AC:

2001

AN:

111827

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0618

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00779

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00422

Gnomad NFE

AF:

0.0000942

Gnomad OTH

AF:

0.0106

GnomAD2 exomes

AF:

0.00541

AC:

979

AN:

180955

AF XY:

0.00349

show subpopulations

Gnomad AFR exome

AF:

0.0656

Gnomad AMR exome

AF:

0.00361

Gnomad ASJ exome

AF:

0.000135

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00177

GnomAD4 exome

AF:

0.00199

AC:

2185

AN:

1098021

Hom.:

Cov.:

AF XY:

0.00160

AC XY:

582

AN XY:

363401

show subpopulations

African (AFR)

AF:

0.0675

AC:

1782

AN:

26402

American (AMR)

AF:

0.00378

AC:

133

AN:

35198

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19365

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.000129

AC:

AN:

54133

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40474

Middle Eastern (MID)

AF:

0.00242

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0000641

AC:

AN:

842023

Other (OTH)

AF:

0.00430

AC:

198

AN:

46088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

109

218

326

435

544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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

AF:

0.0179

AC:

2004

AN:

111881

Hom.:

Cov.:

AF XY:

0.0153

AC XY:

521

AN XY:

34071

show subpopulations

African (AFR)

AF:

0.0618

AC:

1898

AN:

30734

American (AMR)

AF:

0.00778

AC:

AN:

10666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3540

South Asian (SAS)

AF:

0.000374

AC:

AN:

2677

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6115

Middle Eastern (MID)

AF:

0.00463

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000942

AC:

AN:

53068

Other (OTH)

AF:

0.0105

AC:

AN:

1528

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

127

191

254

318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00749

Hom.:

269

Bravo

AF:

0.0210

ESP6500AA

AF:

0.0579

AC:

222

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00602

AC:

731

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 18, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31555317) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.70

CADD

Benign

1.5

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.23

T;.;.;T

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.53

.;T;T;T

MetaRNN

Benign

0.0028

T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.0

N;.;.;N

PhyloP100

-1.2

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.3

D;D;D;D

REVEL

Benign

0.084

Sift

Benign

0.12

T;T;T;T

Sift4G

Benign

0.66

T;T;T;T

Polyphen

0.96

D;B;B;D

Vest4

0.21

MutPred

0.18

Gain of solvent accessibility (P = 0.0155);.;.;Gain of solvent accessibility (P = 0.0155);

MVP

0.37

MPC

0.72

ClinPred

0.0080

GERP RS

-1.1

Varity_R

0.13

gMVP

0.25

Mutation Taster

=95/5

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over