Genetic Variant MAML1:p.Pro88Ala (chr5-179733374-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_014757.5(MAML1):c.262C>G(p.Pro88Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,062,332 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P88T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

MAML1
NM_014757.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.145

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11440426).

BP6

Variant 5-179733374-C-G is Benign according to our data. Variant chr5-179733374-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2327455.Status of the report is criteria_provided_single_submitter, 1 stars.

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.262C>G	p.Pro88Ala	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.262C>G	p.Pro88Ala	missense	Exon 1 of 5	ENSP00000292599.3	Q92585
	MAML1	ENST00000933871.1		c.262C>G	p.Pro88Ala	missense	Exon 1 of 5	ENSP00000603930.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000188

AC:

AN:

1062332

Hom.:

Cov.:

AF XY:

0.00000196

AC XY:

AN XY:

510588

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21102

American (AMR)

AF:

0.00

AC:

AN:

6880

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11968

East Asian (EAS)

AF:

0.00

AC:

AN:

21962

South Asian (SAS)

AF:

0.00

AC:

AN:

23888

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19716

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2688

European-Non Finnish (NFE)

AF:

0.00000219

AC:

AN:

913084

Other (OTH)

AF:

0.00

AC:

AN:

41044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

-0.31

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.31

(source)

DANN

Benign

0.32

DEOGEN2

Benign

0.22

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.040

M_CAP

Pathogenic

0.54

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.40

PhyloP100

0.14

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.18

REVEL

Benign

0.023

Sift

Benign

0.36

Sift4G

Benign

0.11

Polyphen

0.015

Vest4

0.12

MutPred

0.21

Loss of glycosylation at P88 (P = 0.0304)

MVP

0.30

MPC

1.7

ClinPred

0.25

GERP RS

-0.24

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.016

gMVP

0.12

Mutation Taster

=96/4

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over