7-1936744-C-G

Variant names:

• chr7-1936744-C-G
• rs756134237
• NM_001013836.2:c.1750G>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.1750G>C​(p.Val584Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,413,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAD1L1 NM_001013836.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.665
• 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: 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=0.09737563).

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.1750G>C	p.Val584Leu	missense	Exon 17 of 19	NP_001013858.1	Q9Y6D9-1
	MAD1L1	NM_001013837.2		c.1750G>C	p.Val584Leu	missense	Exon 17 of 19	NP_001013859.1	Q9Y6D9-1
	MAD1L1	NM_001304523.2		c.1750G>C	p.Val584Leu	missense	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.1750G>C	p.Val584Leu	missense	Exon 17 of 19	ENSP00000265854.7	Q9Y6D9-1
	MAD1L1	ENST00000406869.5	TSL:1	c.1750G>C	p.Val584Leu	missense	Exon 17 of 19	ENSP00000385334.1	Q9Y6D9-1
	ENSG00000286192	ENST00000651235.1		n.*4510G>C		non_coding_transcript_exon	Exon 22 of 24	ENSP00000498895.1	A0A3B3ITW8

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1413786 Hom.: 0 Cov.: 32 AF XY: 0.00000429 AC XY: 3 AN XY: 699202

African (AFR) AF: 0.00 AC: 0 AN: 32470

American (AMR) AF: 0.00 AC: 0 AN: 37786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25336

East Asian (EAS) AF: 0.00 AC: 0 AN: 37014

South Asian (SAS) AF: 0.00 AC: 0 AN: 80528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1088748

Other (OTH) AF: 0.00 AC: 0 AN: 58608

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.63
DANN	Benign	0.78
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.67
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.012
Sift	Benign	0.23	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.28		Loss of MoRF binding (P = 0.1011)
MVP		0.21
MPC		0.11
ClinPred		0.028	T
GERP RS		-3.2
Varity_R		0.14
gMVP		0.11
Mutation Taster		=87/13	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: rs756134237; hg19: chr7-1976380;