Genetic Variant MAD1L1:c.1998+25614T>C (chr7-1872586-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001013836.2(MAD1L1):c.1998+25614T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 151,964 control chromosomes in the GnomAD database, including 10,636 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.37 ( 10631 hom., cov: 33)

Exomes 𝑓: 0.45 ( 5 hom. )

Consequence

MAD1L1
NM_001013836.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.47

Publications

22 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.03).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAD1L1	NM_001013836.2 link	c.1998+25614T>C		intron_variant	Intron 18 of 18	ENST00000265854.12	NP_001013858.1	Q9Y6D9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAD1L1	ENST00000265854.12 link	c.1998+25614T>C		intron_variant	Intron 18 of 18	1	NM_001013836.2	ENSP00000265854.7		Q9Y6D9-1
ENSG00000286192	ENST00000651235.1 link	n.*4758+25614T>C		intron_variant	Intron 23 of 23			ENSP00000498895.1		A0A3B3ITW8

Frequencies

GnomAD3 genomes

AF:

0.371

AC:

56353

AN:

151808

Hom.:

10619

Cov.:

show subpopulations

Gnomad AFR

AF:

0.321

Gnomad AMI

AF:

0.439

Gnomad AMR

AF:

0.440

Gnomad ASJ

AF:

0.361

Gnomad EAS

AF:

0.463

Gnomad SAS

AF:

0.356

Gnomad FIN

AF:

0.315

Gnomad MID

AF:

0.297

Gnomad NFE

AF:

0.389

Gnomad OTH

AF:

0.385

GnomAD4 exome

AF:

0.447

AC:

AN:

Hom.:

AF XY:

0.471

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.667

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.417

AC:

AN:

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.371

AC:

56396

AN:

151926

Hom.:

10631

Cov.:

AF XY:

0.370

AC XY:

27456

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.321

AC:

13310

AN:

41406

American (AMR)

AF:

0.439

AC:

6715

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.361

AC:

1252

AN:

3470

East Asian (EAS)

AF:

0.464

AC:

2384

AN:

5142

South Asian (SAS)

AF:

0.355

AC:

1711

AN:

4816

European-Finnish (FIN)

AF:

0.315

AC:

3326

AN:

10556

Middle Eastern (MID)

AF:

0.286

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.389

AC:

26413

AN:

67950

Other (OTH)

AF:

0.382

AC:

806

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

1905

3810

5714

7619

9524

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

540

1080

1620

2160

2700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.387

Hom.:

41116

Bravo

AF:

0.380

Asia WGS

AF:

0.398

AC:

1384

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.40

(source)

DANN

Benign

0.086

PhyloP100

-3.5

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over