Variant 5-179733353-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -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. 13/21 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

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 made for transcript

Verdict is Benign. Variant got -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 id is 2344167.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 56 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAML1	NM_014757.5 linkuse as main transcript	c.241A>C	p.Thr81Pro	missense_variant	1/5	ENST00000292599.4	NP_055572.1	Q92585

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAML1	ENST00000292599.4 linkuse as main transcript	c.241A>C	p.Thr81Pro	missense_variant	1/5	1	NM_014757.5	ENSP00000292599.3		Q92585

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

GnomAD3 exomes

AF:

0.000402

AC:

AN:

27336

Hom.:

AF XY:

0.000370

AC XY:

AN XY:

16204

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 SAS 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

Gnomad4 AFR exome

AF:

0.00195

Gnomad4 AMR exome

AF:

0.000220

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000437

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000368

Gnomad4 OTH exome

AF:

0.000773

GnomAD4 genome

AF:

0.000375

AC:

AN:

149196

Hom.:

Cov.:

AF XY:

0.000357

AC XY:

AN XY:

72790

show subpopulations

Gnomad4 AFR

AF:

0.000317

Gnomad4 AMR

AF:

0.000200

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000197

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000567

Gnomad4 OTH

AF:

0.000484

Alfa

AF:

0.000498

Hom.:

Bravo

AF:

0.000359

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.047

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.57

CADD

Benign

0.080

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

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

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