dbSNP rs1801368: MAD1L1:p.Arg558Pro (chr7-1936821-C-G) – 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_001013836.2(MAD1L1):c.1673G>C(p.Arg558Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,702 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. 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. R558C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

MAD1L1
NM_001013836.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.140

Publications

56 publications found

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 Gene-Disease associations (from GenCC):

mosaic variegated aneuploidy syndrome 7 with inflammation and tumor predisposition
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
familial prostate carcinoma
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

MAD1L1 links:

ENSG00000286192 (HGNC:):

ENSG00000286192 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=0.1679638).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAD1L1	NM_001013836.2 link	c.1673G>C	p.Arg558Pro	missense_variant	Exon 17 of 19	ENST00000265854.12	NP_001013858.1	Q9Y6D9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAD1L1	ENST00000265854.12 link	c.1673G>C	p.Arg558Pro	missense_variant	Exon 17 of 19	1	NM_001013836.2	ENSP00000265854.7	Q9Y6D9-1
ENSG00000286192	ENST00000651235.1 link	n.*4433G>C		non_coding_transcript_exon_variant	Exon 22 of 24			ENSP00000498895.1	A0A3B3ITW8
ENSG00000286192	ENST00000651235.1 link	n.*4433G>C		3_prime_UTR_variant	Exon 22 of 24			ENSP00000498895.1	A0A3B3ITW8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1447702

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

718854

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33356

American (AMR)

AF:

0.00

AC:

AN:

42594

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25826

East Asian (EAS)

AF:

0.00

AC:

AN:

39080

South Asian (SAS)

AF:

0.00

AC:

AN:

83820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51484

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1105992

Other (OTH)

AF:

0.0000167

AC:

AN:

59806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.36

T;.;T;T;.;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.72

T;T;.;.;.;T

M_CAP

Benign

0.034

MetaRNN

Benign

0.17

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;L;L;.;.

PhyloP100

-0.14

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

N;N;N;N;N;N

REVEL

Benign

0.063

Sift

Benign

0.19

T;T;T;T;T;T

Sift4G

Benign

0.30

T;T;T;T;T;T

Polyphen

0.42

B;.;B;B;.;.

Vest4

0.50

MutPred

0.55

Loss of MoRF binding (P = 0.0024);.;Loss of MoRF binding (P = 0.0024);Loss of MoRF binding (P = 0.0024);.;.;

MVP

0.47

MPC

0.26

ClinPred

0.21

GERP RS

-0.0015

Varity_R

0.33

gMVP

0.59

Mutation Taster

=76/24

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over