Genetic Variant MAD1L1:c.1999-30671C>G (chr7-1846899-G-C) – 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.1999-30671C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 273,910 control chromosomes in the GnomAD database, including 16,938 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 0.36 ( 10227 hom., cov: 34)

Exomes 𝑓: 0.32 ( 6711 hom. )

Consequence

MAD1L1
NM_001013836.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.18

Publications

16 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAD1L1	NM_001013836.2 link	c.1999-30671C>G		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.1999-30671C>G		intron_variant	Intron 18 of 18	1	NM_001013836.2	ENSP00000265854.7		Q9Y6D9-1
ENSG00000286192	ENST00000651235.1 link	n.*4759-30671C>G		intron_variant	Intron 23 of 23			ENSP00000498895.1		A0A3B3ITW8

Frequencies

GnomAD3 genomes

AF:

0.364

AC:

55288

AN:

152070

Hom.:

10217

Cov.:

show subpopulations

Gnomad AFR

AF:

0.386

Gnomad AMI

AF:

0.418

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.319

Gnomad EAS

AF:

0.447

Gnomad SAS

AF:

0.417

Gnomad FIN

AF:

0.270

Gnomad MID

AF:

0.294

Gnomad NFE

AF:

0.337

Gnomad OTH

AF:

0.379

GnomAD4 exome

AF:

0.321

AC:

39051

AN:

121722

Hom.:

6711

Cov.:

AF XY:

0.327

AC XY:

21388

AN XY:

65484

show subpopulations

African (AFR)

AF:

0.336

AC:

708

AN:

2110

American (AMR)

AF:

0.438

AC:

1769

AN:

4042

Ashkenazi Jewish (ASJ)

AF:

0.266

AC:

728

AN:

2736

East Asian (EAS)

AF:

0.396

AC:

1303

AN:

3294

South Asian (SAS)

AF:

0.363

AC:

8490

AN:

23394

European-Finnish (FIN)

AF:

0.253

AC:

1582

AN:

6250

Middle Eastern (MID)

AF:

0.233

AC:

101

AN:

434

European-Non Finnish (NFE)

AF:

0.307

AC:

22530

AN:

73472

Other (OTH)

AF:

0.307

AC:

1840

AN:

5990

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1100

2201

3301

4402

5502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

190

380

570

760

950

<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:

0.363

AC:

55311

AN:

152188

Hom.:

10227

Cov.:

AF XY:

0.364

AC XY:

27082

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.386

AC:

16021

AN:

41510

American (AMR)

AF:

0.445

AC:

6810

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.319

AC:

1107

AN:

3472

East Asian (EAS)

AF:

0.448

AC:

2317

AN:

5172

South Asian (SAS)

AF:

0.417

AC:

2014

AN:

4832

European-Finnish (FIN)

AF:

0.270

AC:

2860

AN:

10596

Middle Eastern (MID)

AF:

0.282

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.337

AC:

22924

AN:

67998

Other (OTH)

AF:

0.376

AC:

794

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1889

3778

5667

7556

9445

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

542

1084

1626

2168

2710

<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:

0.332

Hom.:

1046

Bravo

AF:

0.382

Asia WGS

AF:

0.421

AC:

1461

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.46

PhyloP100

1.2

Mutation Taster

=99/1

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