rs2073043

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.1985A>G(p.Asn662Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,202,243 control chromosomes in the GnomAD database, including 7,994 homozygotes. There are 51,547 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 583 hom., 3233 hem., cov: 23)

Exomes 𝑓: 0.14 ( 7411 hom. 48314 hem. )

Consequence

MAMLD1
NM_005491.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.441

Publications

18 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=0.0011407137).

BP6

Variant X-150473747-A-G is Benign according to our data. Variant chrX-150473747-A-G is described in ClinVar as Benign. ClinVar VariationId is 1598681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

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
MAMLD1	NM_005491.5	MANE Select	c.1985A>G	p.Asn662Ser	missense	Exon 5 of 8	NP_005482.2
MAMLD1	NM_001400515.1		c.1985A>G	p.Asn662Ser	missense	Exon 6 of 9	NP_001387444.1
MAMLD1	NM_001177466.3		c.1910A>G	p.Asn637Ser	missense	Exon 5 of 8	NP_001170937.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MAMLD1	ENST00000370401.7	TSL:5 MANE Select	c.1985A>G	p.Asn662Ser	missense	Exon 5 of 8	ENSP00000359428.2
MAMLD1	ENST00000426613.5	TSL:1	c.1910A>G	p.Asn637Ser	missense	Exon 5 of 8	ENSP00000397438.2
MAMLD1	ENST00000682253.1		c.1985A>G	p.Asn662Ser	missense	Exon 5 of 8	ENSP00000506890.1

Frequencies

GnomAD3 genomes

AF:

0.104

AC:

11515

AN:

110226

Hom.:

581

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0264

Gnomad AMI

AF:

0.208

Gnomad AMR

AF:

0.112

Gnomad ASJ

AF:

0.155

Gnomad EAS

AF:

0.0517

Gnomad SAS

AF:

0.0400

Gnomad FIN

AF:

0.119

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.149

Gnomad OTH

AF:

0.106

GnomAD2 exomes

AF:

0.110

AC:

20147

AN:

183205

AF XY:

0.112

show subpopulations

Gnomad AFR exome

AF:

0.0233

Gnomad AMR exome

AF:

0.101

Gnomad ASJ exome

AF:

0.157

Gnomad EAS exome

AF:

0.0573

Gnomad FIN exome

AF:

0.125

Gnomad NFE exome

AF:

0.142

Gnomad OTH exome

AF:

0.117

GnomAD4 exome

AF:

0.136

AC:

148987

AN:

1091963

Hom.:

7411

Cov.:

AF XY:

0.135

AC XY:

48314

AN XY:

357593

show subpopulations

African (AFR)

AF:

0.0244

AC:

642

AN:

26285

American (AMR)

AF:

0.102

AC:

3604

AN:

35194

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

3073

AN:

19347

East Asian (EAS)

AF:

0.0541

AC:

1633

AN:

30189

South Asian (SAS)

AF:

0.0527

AC:

2846

AN:

53998

European-Finnish (FIN)

AF:

0.127

AC:

5153

AN:

40488

Middle Eastern (MID)

AF:

0.113

AC:

467

AN:

4116

European-Non Finnish (NFE)

AF:

0.150

AC:

125772

AN:

836441

Other (OTH)

AF:

0.126

AC:

5797

AN:

45905

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

4496

8992

13487

17983

22479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4632

9264

13896

18528

23160

<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:

0.104

AC:

11515

AN:

110280

Hom.:

583

Cov.:

AF XY:

0.0987

AC XY:

3233

AN XY:

32760

show subpopulations

African (AFR)

AF:

0.0263

AC:

797

AN:

30269

American (AMR)

AF:

0.112

AC:

1172

AN:

10489

Ashkenazi Jewish (ASJ)

AF:

0.155

AC:

405

AN:

2619

East Asian (EAS)

AF:

0.0519

AC:

180

AN:

3471

South Asian (SAS)

AF:

0.0405

AC:

104

AN:

2568

European-Finnish (FIN)

AF:

0.119

AC:

699

AN:

5893

Middle Eastern (MID)

AF:

0.147

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.149

AC:

7831

AN:

52591

Other (OTH)

AF:

0.104

AC:

156

AN:

1494

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

380

760

1139

1519

1899

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<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:

0.114

Hom.:

3217

Bravo

AF:

0.102

TwinsUK

AF:

0.148

AC:

549

ALSPAC

AF:

0.144

AC:

417

ESP6500AA

AF:

0.0300

AC:

115

ESP6500EA

AF:

0.145

AC:

976

ExAC

AF:

0.110

AC:

13328

EpiCase

AF:

0.144

EpiControl

AF:

0.142

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.80

CADD

Benign

9.3

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.040

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0011

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

0.44

PROVEAN

Benign

-0.45

REVEL

Benign

0.032

Sift

Benign

0.039

Sift4G

Benign

0.65

Polyphen

0.34

Vest4

0.025

ClinPred

0.0038

GERP RS

2.5

Varity_R

0.053

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over