rs6461049

Variant names:

• chr7-1977810-C-T
• rs6461049
• NM_001013836.2:c.1505+2643G>A

Variant summary

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

The NM_001013836.2(MAD1L1):​c.1505+2643G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.559 in 152,156 control chromosomes in the GnomAD database, including 24,145 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 0.56 (24145 hom., cov: 35)
• Consequence: MAD1L1 NM_001013836.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.21
• Publications: 35 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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAD1L1	NM_001013836.2	c.1505+2643G>A		intron_variant	Intron 15 of 18	ENST00000265854.12	NP_001013858.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAD1L1	ENST00000265854.12	c.1505+2643G>A		intron_variant	Intron 15 of 18	1	NM_001013836.2	ENSP00000265854.7
ENSG00000286192	ENST00000651235.1	n.*4265+2643G>A		intron_variant	Intron 20 of 23			ENSP00000498895.1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 85033 AN: 152038 Hom.: 24126 Cov.: 35

Gnomad AFR AF: 0.563

Gnomad AMI AF: 0.671

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.651

Gnomad MID AF: 0.684

Gnomad NFE AF: 0.575

Gnomad OTH AF: 0.553

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

GnomAD4 genome AF: 0.559 AC: 85085 AN: 152156 Hom.: 24145 Cov.: 35 AF XY: 0.560 AC XY: 41640 AN XY: 74386

African (AFR) AF: 0.563 AC: 23363 AN: 41498

American (AMR) AF: 0.430 AC: 6576 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2145 AN: 3470

East Asian (EAS) AF: 0.434 AC: 2236 AN: 5156

South Asian (SAS) AF: 0.580 AC: 2802 AN: 4830

European-Finnish (FIN) AF: 0.651 AC: 6903 AN: 10596

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.575 AC: 39070 AN: 67988

Other (OTH) AF: 0.556 AC: 1173 AN: 2110

Alfa AF: 0.562 Hom.: 87998

Bravo AF: 0.540

Asia WGS AF: 0.516 AC: 1794 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.040
DANN	Benign	0.57
PhyloP100		-1.2
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: rs6461049; hg19: chr7-2017445; COSMIC: COSV56229981; COSMIC: COSV56229981;