rs4721295

Variant names:

• chr7-1997034-T-G
• rs4721295
• NM_001013836.2:c.1416+5031A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001013836.2(MAD1L1):​c.1416+5031A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 152,052 control chromosomes in the GnomAD database, including 9,557 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 0.34 (9557 hom., cov: 33)
• Consequence: MAD1L1 NM_001013836.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.520
• Publications: 25 publications found

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)

ENSG00000286192 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAD1L1	NM_001013836.2	MANE Select	c.1416+5031A>C		intron	N/A	NP_001013858.1
	MAD1L1	NM_001013837.2		c.1416+5031A>C		intron	N/A	NP_001013859.1
	MAD1L1	NM_001304523.2		c.1416+5031A>C		intron	N/A	NP_001291452.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAD1L1	ENST00000265854.12	TSL:1 MANE Select	c.1416+5031A>C		intron	N/A	ENSP00000265854.7
	MAD1L1	ENST00000406869.5	TSL:1	c.1416+5031A>C		intron	N/A	ENSP00000385334.1
	ENSG00000286192	ENST00000651235.1		n.*4176+5031A>C		intron	N/A	ENSP00000498895.1

Frequencies

GnomAD3 genomes AF: 0.336 AC: 51098 AN: 151934 Hom.: 9555 Cov.: 33

Gnomad AFR AF: 0.176

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.448

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.564

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.370

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.336 AC: 51098 AN: 152052 Hom.: 9557 Cov.: 33 AF XY: 0.337 AC XY: 25065 AN XY: 74320

African (AFR) AF: 0.175 AC: 7268 AN: 41478

American (AMR) AF: 0.448 AC: 6850 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1349 AN: 3470

East Asian (EAS) AF: 0.565 AC: 2928 AN: 5180

South Asian (SAS) AF: 0.336 AC: 1615 AN: 4806

European-Finnish (FIN) AF: 0.335 AC: 3535 AN: 10554

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.390 AC: 26533 AN: 67974

Other (OTH) AF: 0.368 AC: 775 AN: 2108

Alfa AF: 0.371 Hom.: 19643

Bravo AF: 0.339

Asia WGS AF: 0.428 AC: 1482 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.88
DANN	Benign	0.33
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4721295; hg19: chr7-2036669;