chr14-24506119-A-T

Variant names:

• chr14-24506119-A-T
• rs141243253
• NM_001836.5:c.509T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001836.5(CMA1):​c.509T>A​(p.Met170Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 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. M170T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CMA1 NM_001836.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56
• Publications: 0 publications found

Genes affected

CMA1 (HGNC:2097): (chymase 1) This gene encodes a chymotryptic serine proteinase that belongs to the peptidase family S1. It is expressed in mast cells and is thought to function in the degradation of the extracellular matrix, the regulation of submucosal gland secretion, and the generation of vasoactive peptides. In the heart and blood vessels, this protein, rather than angiotensin converting enzyme, is largely responsible for converting angiotensin I to the vasoactive peptide angiotensin II. Alternative splicing results in multiple variants. [provided by RefSeq, Apr 2015]

ENSG00000258744 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001836.5. 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
	CMA1	NM_001836.5	MANE Select	c.509T>A	p.Met170Lys	missense	Exon 4 of 5	NP_001827.1	P23946-1
	CMA1	NM_001308083.2		c.176T>A	p.Met59Lys	missense	Exon 3 of 4	NP_001295012.1	P23946-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CMA1	ENST00000250378.7	TSL:1 MANE Select	c.509T>A	p.Met170Lys	missense	Exon 4 of 5	ENSP00000250378.3	P23946-1
	CMA1	ENST00000206446.4	TSL:1	c.176T>A	p.Met59Lys	missense	Exon 3 of 4	ENSP00000206446.4	P23946-2
	ENSG00000258744	ENST00000555109.2	TSL:5	n.552-2015A>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.6
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.62
Sift	Benign	0.066	T
Sift4G	Benign	0.40	T
Polyphen		0.83	P
Vest4		0.58
MutPred		0.89		Loss of stability (P = 0.0102)
MVP		0.99
MPC		0.0036
ClinPred		0.94	D
GERP RS		4.7
Varity_R		0.63
gMVP		0.75
Mutation Taster		=68/32	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: rs141243253; hg19: chr14-24975325;