4-120060185-C-A

Variant names:

• chr4-120060185-C-A
• rs779431364
• NM_002358.4:c.551G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002358.4(MAD2L1):​c.551G>T​(p.Arg184Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,142 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R184H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MAD2L1 NM_002358.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.43
• Publications: 0 publications found

Genes affected

MAD2L1 (HGNC:6763): (mitotic arrest deficient 2 like 1) MAD2L1 is a component of the mitotic spindle assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. MAD2L1 is related to the MAD2L2 gene located on chromosome 1. A MAD2 pseudogene has been mapped to chromosome 14. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002358.4. 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
	MAD2L1	NM_002358.4	MANE Select	c.551G>T	p.Arg184Leu	missense	Exon 5 of 5	NP_002349.1	Q13257-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAD2L1	ENST00000296509.11	TSL:1 MANE Select	c.551G>T	p.Arg184Leu	missense	Exon 5 of 5	ENSP00000296509.5	Q13257-1
	MAD2L1	ENST00000333047.9	TSL:1	n.*157G>T		non_coding_transcript_exon	Exon 4 of 4	ENSP00000332295.5	Q13257-2
	MAD2L1	ENST00000333047.9	TSL:1	n.*157G>T		3_prime_UTR	Exon 4 of 4	ENSP00000332295.5	Q13257-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460142 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726402

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5004

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111456

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.5	M
PhyloP100		7.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.78		Loss of MoRF binding (P = 0.0247)
MVP		0.76
MPC		1.6
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.79
Mutation Taster		=13/87	disease causing

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: rs779431364; hg19: chr4-120981340;