chr7-2225526-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001013836.2(MAD1L1):c.175C>T(p.Arg59Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00445 in 1,613,878 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0046 ( 20 hom. )

Consequence

MAD1L1
NM_001013836.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:2

Conservation

PhyloP100: 5.79

Publications

25 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008932233).

BP6

Variant 7-2225526-G-A is Benign according to our data. Variant chr7-2225526-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 6920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001013836.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MAD1L1	NM_001013836.2	MANE Select	c.175C>T	p.Arg59Cys	missense	Exon 4 of 19	NP_001013858.1
MAD1L1	NM_001013837.2		c.175C>T	p.Arg59Cys	missense	Exon 4 of 19	NP_001013859.1
MAD1L1	NM_001304523.2		c.175C>T	p.Arg59Cys	missense	Exon 3 of 18	NP_001291452.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MAD1L1	ENST00000265854.12	TSL:1 MANE Select	c.175C>T	p.Arg59Cys	missense	Exon 4 of 19	ENSP00000265854.7
MAD1L1	ENST00000406869.5	TSL:1	c.175C>T	p.Arg59Cys	missense	Exon 4 of 19	ENSP00000385334.1
ENSG00000286192	ENST00000651235.1		n.*2583C>T		non_coding_transcript_exon	Exon 8 of 24	ENSP00000498895.1

Frequencies

GnomAD3 genomes

AF:

0.00297

AC:

452

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00544

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00308

AC:

767

AN:

249138

AF XY:

0.00329

show subpopulations

Gnomad AFR exome

AF:

0.000646

Gnomad AMR exome

AF:

0.000782

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00183

Gnomad NFE exome

AF:

0.00591

Gnomad OTH exome

AF:

0.00347

GnomAD4 exome

AF:

0.00460

AC:

6724

AN:

1461576

Hom.:

Cov.:

AF XY:

0.00452

AC XY:

3290

AN XY:

727106

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33480

American (AMR)

AF:

0.000760

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00284

AC:

151

AN:

53144

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00569

AC:

6328

AN:

1111986

Other (OTH)

AF:

0.00321

AC:

194

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

355

710

1066

1421

1776

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

236

472

708

944

1180

<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:

0.00297

AC:

452

AN:

152302

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00101

AC:

AN:

41562

American (AMR)

AF:

0.000980

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00544

AC:

370

AN:

68032

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00468

Hom.:

Bravo

AF:

0.00265

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000715

AC:

ESP6500EA

AF:

0.00556

AC:

ExAC

AF:

0.00350

AC:

424

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Prostate cancer (1)

Prostate cancer, somatic (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.42

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.026

MetaRNN

Benign

0.0089

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.5

PhyloP100

5.8

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.3

REVEL

Benign

0.27

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.040

Polyphen

1.0

Vest4

0.38

MVP

0.55

MPC

0.61

ClinPred

0.035

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.19

Mutation Taster

=82/18

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over