Variant 7-1816144-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001013836.2(MAD1L1):c.2083C>T(p.Arg695Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000725 in 1,613,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 0 hom. )

Consequence

MAD1L1
NM_001013836.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.39

Variant links:

Genes affected

MAD1L1 (HGNC:6762): (mitotic arrest deficient 1 like 1) MAD1L1 is a component of the mitotic spindle-assembly checkpoint that prevents the onset of anaphase until all chromosome are properly aligned at the metaphase plate. MAD1L1 functions as a homodimer and interacts with MAD2L1. MAD1L1 may play a role in cell cycle control and tumor suppression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

MAD1L1 links:

ENSG00000286192 (HGNC:):

ENSG00000286192 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15028763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAD1L1	NM_001013836.2 linkuse as main transcript	c.2083C>T	p.Arg695Trp	missense_variant	19/19	ENST00000265854.12	NP_001013858.1	Q9Y6D9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MAD1L1	ENST00000265854.12 linkuse as main transcript	c.2083C>T	p.Arg695Trp	missense_variant	19/19	1	NM_001013836.2	ENSP00000265854.7	Q9Y6D9-1
ENSG00000286192	ENST00000651235.1 linkuse as main transcript	n.*4843C>T		non_coding_transcript_exon_variant	24/24			ENSP00000498895.1	A0A3B3ITW8
ENSG00000286192	ENST00000651235.1 linkuse as main transcript	n.*4843C>T		3_prime_UTR_variant	24/24			ENSP00000498895.1	A0A3B3ITW8

Frequencies

GnomAD3 genomes

AF:

0.000374

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000373

AC:

AN:

249034

Hom.:

AF XY:

0.000362

AC XY:

AN XY:

135208

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000770

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000762

AC:

1113

AN:

1460926

Hom.:

Cov.:

AF XY:

0.000751

AC XY:

546

AN XY:

726804

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000132

Gnomad4 NFE exome

AF:

0.000965

Gnomad4 OTH exome

AF:

0.000448

GnomAD4 genome

AF:

0.000374

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000442

Hom.:

Bravo

AF:

0.000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000832

AC:

ExAC

AF:

0.000330

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000534

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The c.2083C>T (p.R695W) alteration is located in exon 19 (coding exon 17) of the MAD1L1 gene. This alteration results from a C to T substitution at nucleotide position 2083, causing the arginine (R) at amino acid position 695 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.;T;T;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.87

D;D;.;.;.

M_CAP

Benign

0.023

MetaRNN

Benign

0.15

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;.;N;N;.

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.5

N;N;N;N;N

REVEL

Benign

0.078

Sift

Benign

0.065

T;T;T;T;T

Sift4G

Benign

0.19

T;T;T;T;T

Polyphen

0.87

P;.;P;P;.

Vest4

0.22

MVP

0.51

MPC

0.21

ClinPred

0.12

GERP RS

4.0

Varity_R

0.14

gMVP

0.50

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