Genetic Variant MAML1:p.Thr81Pro (chr5-179733353-A-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_014757.5(MAML1):c.241A>C(p.Thr81Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,278,692 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 1 hom. )

Consequence

MAML1
NM_014757.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.533

Publications

1 publications found

Variant links:

Genes affected

MAML1 (HGNC:13632): (mastermind like transcriptional coactivator 1) This protein is the human homolog of mastermind, a Drosophila protein that plays a role in the Notch signaling pathway involved in cell-fate determination. There is in vitro evidence that the human homolog forms a complex with the intracellular portion of human Notch receptors and can increase expression of a Notch-induced gene. This evidence supports its proposed function as a transcriptional co-activator in the Notch signaling pathway. [provided by RefSeq, Jul 2008]

MAML1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03294733).

BP6

Variant 5-179733353-A-C is Benign according to our data. Variant chr5-179733353-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2344167.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 56 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014757.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAML1	NM_014757.5	MANE Select	c.241A>C	p.Thr81Pro	missense	Exon 1 of 5	NP_055572.1	Q92585

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAML1	ENST00000292599.4	TSL:1 MANE Select	c.241A>C	p.Thr81Pro	missense	Exon 1 of 5	ENSP00000292599.3	Q92585
	MAML1	ENST00000933871.1		c.241A>C	p.Thr81Pro	missense	Exon 1 of 5	ENSP00000603930.1

Frequencies

GnomAD3 genomes

AF:

0.000376

AC:

AN:

149088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000318

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000201

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000567

Gnomad OTH

AF:

0.000489

GnomAD2 exomes

AF:

0.000402

AC:

AN:

27336

AF XY:

0.000370

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.00105

GnomAD4 exome

AF:

0.000398

AC:

449

AN:

1129496

Hom.:

Cov.:

AF XY:

0.000414

AC XY:

228

AN XY:

550158

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

22560

American (AMR)

AF:

0.000220

AC:

AN:

13658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15146

East Asian (EAS)

AF:

0.0000437

AC:

AN:

22896

South Asian (SAS)

AF:

0.00

AC:

AN:

41718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23784

Middle Eastern (MID)

AF:

0.00667

AC:

AN:

3000

European-Non Finnish (NFE)

AF:

0.000368

AC:

347

AN:

942774

Other (OTH)

AF:

0.000773

AC:

AN:

43960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000375

AC:

AN:

149196

Hom.:

Cov.:

AF XY:

0.000357

AC XY:

AN XY:

72790

show subpopulations

African (AFR)

AF:

0.000317

AC:

AN:

40970

American (AMR)

AF:

0.000200

AC:

AN:

14968

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3440

East Asian (EAS)

AF:

0.000197

AC:

AN:

5076

South Asian (SAS)

AF:

0.00

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9666

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000567

AC:

AN:

67030

Other (OTH)

AF:

0.000484

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.000498

Hom.:

Bravo

AF:

0.000359

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.080

(source)

DANN

Benign

0.30

DEOGEN2

Benign

0.22

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0051

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.033

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.81

PhyloP100

-0.53

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

0.48

REVEL

Benign

0.013

Sift

Benign

0.56

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.078

MutPred

0.19

Loss of phosphorylation at T81 (P = 0.0088)

MVP

0.21

MPC

2.2

ClinPred

0.032

GERP RS

-0.80

Varity_R

0.094

gMVP

0.20

Mutation Taster

=95/5

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over