chr7-1936821-C-G

Variant names:

• chr7-1936821-C-G
• rs1801368
• NM_001013836.2:c.1673G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001013836.2(MAD1L1):​c.1673G>C​(p.Arg558Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R558C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAD1L1 NM_001013836.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.140
• Publications: 56 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1679638).

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.1673G>C	p.Arg558Pro	missense	Exon 17 of 19	NP_001013858.1
	MAD1L1	NM_001013837.2		c.1673G>C	p.Arg558Pro	missense	Exon 17 of 19	NP_001013859.1
	MAD1L1	NM_001304523.2		c.1673G>C	p.Arg558Pro	missense	Exon 16 of 18	NP_001291452.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAD1L1	ENST00000265854.12	TSL:1 MANE Select	c.1673G>C	p.Arg558Pro	missense	Exon 17 of 19	ENSP00000265854.7
	MAD1L1	ENST00000406869.5	TSL:1	c.1673G>C	p.Arg558Pro	missense	Exon 17 of 19	ENSP00000385334.1
	ENSG00000286192	ENST00000651235.1		n.*4433G>C		non_coding_transcript_exon	Exon 22 of 24	ENSP00000498895.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447702 Hom.: 0 Cov.: 62 AF XY: 0.00000278 AC XY: 2 AN XY: 718854

African (AFR) AF: 0.00 AC: 0 AN: 33356

American (AMR) AF: 0.00 AC: 0 AN: 42594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25826

East Asian (EAS) AF: 0.00 AC: 0 AN: 39080

South Asian (SAS) AF: 0.00 AC: 0 AN: 83820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105992

Other (OTH) AF: 0.0000167 AC: 1 AN: 59806

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.14
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.063
Sift	Benign	0.19	T
Sift4G	Benign	0.30	T
Polyphen		0.42	B
Vest4		0.50
MutPred		0.55		Loss of MoRF binding (P = 0.0024)
MVP		0.47
MPC		0.26
ClinPred		0.21	T
GERP RS		-0.0015
Varity_R		0.33
gMVP		0.59
Mutation Taster		=76/24	polymorphism

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: rs1801368; hg19: chr7-1976457;