7-1936704-G-T

Variant names:

• chr7-1936704-G-T
• rs373139029
• NM_001013836.2:c.1790C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001013836.2(MAD1L1):​c.1790C>A​(p.Ser597*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,403,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: MAD1L1 NM_001013836.2 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.42
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAD1L1	NM_001013836.2	MANE Select	c.1790C>A	p.Ser597*	stop_gained	Exon 17 of 19	NP_001013858.1	Q9Y6D9-1
	MAD1L1	NM_001013837.2		c.1790C>A	p.Ser597*	stop_gained	Exon 17 of 19	NP_001013859.1	Q9Y6D9-1
	MAD1L1	NM_001304523.2		c.1790C>A	p.Ser597*	stop_gained	Exon 16 of 18	NP_001291452.1	Q9Y6D9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAD1L1	ENST00000265854.12	TSL:1 MANE Select	c.1790C>A	p.Ser597*	stop_gained	Exon 17 of 19	ENSP00000265854.7	Q9Y6D9-1
	MAD1L1	ENST00000406869.5	TSL:1	c.1790C>A	p.Ser597*	stop_gained	Exon 17 of 19	ENSP00000385334.1	Q9Y6D9-1
	ENSG00000286192	ENST00000651235.1		n.*4550C>A		non_coding_transcript_exon	Exon 22 of 24	ENSP00000498895.1	A0A3B3ITW8

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403586 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 693178

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32092

American (AMR) AF: 0.00 AC: 0 AN: 36640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25224

East Asian (EAS) AF: 0.0000275 AC: 1 AN: 36406

South Asian (SAS) AF: 0.00 AC: 0 AN: 79694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5508

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082980

Other (OTH) AF: 0.00 AC: 0 AN: 58226

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	51
DANN	Uncertain	0.99
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		7.4
Vest4		0.89
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=3/197	disease causing (fs/PTC)

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: rs373139029; hg19: chr7-1976340;