Genetic Variant MAD1L1:p.Cys568Tyr (chr7-1936791-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001013836.2(MAD1L1):c.1703G>A(p.Cys568Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,585,644 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

MAD1L1
NM_001013836.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.24

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAD1L1	NM_001013836.2 link	c.1703G>A	p.Cys568Tyr	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.1703G>A	p.Cys568Tyr	missense_variant	Exon 17 of 19	1	NM_001013836.2	ENSP00000265854.7	Q9Y6D9-1
ENSG00000286192	ENST00000651235.1 link	n.*4463G>A		non_coding_transcript_exon_variant	Exon 22 of 24			ENSP00000498895.1	A0A3B3ITW8
ENSG00000286192	ENST00000651235.1 link	n.*4463G>A		3_prime_UTR_variant	Exon 22 of 24			ENSP00000498895.1	A0A3B3ITW8

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152266

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000251

AC:

AN:

199318

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

108198

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000577

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000977

AC:

AN:

1433378

Hom.:

Cov.:

AF XY:

0.00000844

AC XY:

AN XY:

710526

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:

0.0000109

Gnomad4 OTH exome

AF:

0.0000337

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.00000833

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1703G>A (p.C568Y) alteration is located in exon 17 (coding exon 15) of the MAD1L1 gene. This alteration results from a G to A substitution at nucleotide position 1703, causing the cysteine (C) at amino acid position 568 to be replaced by a tyrosine (Y). 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

Uncertain

0.40

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;.;T;T;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.78

T;T;.;.;.;D

M_CAP

Benign

0.032

MetaRNN

Uncertain

0.69

D;D;D;D;D;D

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.6

M;.;M;M;.;.

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.4

D;D;D;D;D;D

REVEL

Uncertain

0.29

Sift

Uncertain

0.0090

D;D;D;D;D;D

Sift4G

Benign

0.80

T;T;T;T;T;D

Polyphen

1.0

D;.;D;D;.;.

Vest4

0.54

MutPred

0.61

Gain of phosphorylation at C568 (P = 0.0596);.;Gain of phosphorylation at C568 (P = 0.0596);Gain of phosphorylation at C568 (P = 0.0596);.;.;

MVP

0.78

MPC

0.23

ClinPred

0.70

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.65

gMVP

0.46

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