Genetic Variant NM_014757.5:c.289G>A (chr5-179733401-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014757.5(MAML1):c.289G>A(p.Gly97Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000999 in 1,000,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G97R) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000010 ( 0 hom. )

Consequence

MAML1
NM_014757.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.20

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15348086).

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.289G>A	p.Gly97Ser	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.289G>A	p.Gly97Ser	missense	Exon 1 of 5	ENSP00000292599.3	Q92585
	MAML1	ENST00000933871.1		c.289G>A	p.Gly97Ser	missense	Exon 1 of 5	ENSP00000603930.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.99e-7

AC:

AN:

1000746

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

476788

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19640

American (AMR)

AF:

0.00

AC:

AN:

5506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10078

East Asian (EAS)

AF:

0.00

AC:

AN:

16782

South Asian (SAS)

AF:

0.00

AC:

AN:

19314

European-Finnish (FIN)

AF:

0.00

AC:

AN:

15648

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2434

European-Non Finnish (NFE)

AF:

0.00000114

AC:

AN:

873938

Other (OTH)

AF:

0.00

AC:

AN:

37406

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.24

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.35

PhyloP100

2.2

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.050

REVEL

Benign

0.042

Sift

Benign

0.26

Sift4G

Benign

0.56

Polyphen

0.026

Vest4

0.15

MutPred

0.29

Loss of catalytic residue at G97 (P = 0.0012)

MVP

0.38

MPC

1.8

ClinPred

0.75

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.21

Mutation Taster

=86/14

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over