rs779421821

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001013836.2(MAD1L1):​c.1958C>T​(p.Ser653Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MAD1L1
NM_001013836.2 missense

Scores

12
6
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.41
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.959

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAD1L1NM_001013836.2 linkc.1958C>T p.Ser653Leu missense_variant Exon 18 of 19 ENST00000265854.12 NP_001013858.1 Q9Y6D9-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAD1L1ENST00000265854.12 linkc.1958C>T p.Ser653Leu missense_variant Exon 18 of 19 1 NM_001013836.2 ENSP00000265854.7 Q9Y6D9-1
ENSG00000286192ENST00000651235.1 linkn.*4718C>T non_coding_transcript_exon_variant Exon 23 of 24 ENSP00000498895.1 A0A3B3ITW8
ENSG00000286192ENST00000651235.1 linkn.*4718C>T 3_prime_UTR_variant Exon 23 of 24 ENSP00000498895.1 A0A3B3ITW8

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461606
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727074
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.86
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.54
D;.;D;D;.;.
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;.;.;.;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.96
D;D;D;D;D;D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Pathogenic
2.9
M;.;M;M;.;.
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-5.5
D;D;D;D;D;D
REVEL
Pathogenic
0.70
Sift
Pathogenic
0.0
D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
1.0
D;.;D;D;.;.
Vest4
0.99
MutPred
0.79
Loss of catalytic residue at S653 (P = 0.0479);.;Loss of catalytic residue at S653 (P = 0.0479);Loss of catalytic residue at S653 (P = 0.0479);.;.;
MVP
0.84
MPC
0.52
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.89
gMVP
0.80

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.

Other links and lift over

dbSNP: rs779421821; hg19: chr7-1937876; API