14-24507429-C-G

Position:

• chr14-24507429-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000250378.7(CMA1):​c.136G>C​(p.Gly46Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,614,156 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (20 hom.)
• Consequence: CMA1 ENST00000250378.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.250

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0063990355).
• BP6: Variant 14-24507429-C-G is Benign according to our data. Variant chr14-24507429-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 708801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CMA1	NM_001836.5	c.136G>C	p.Gly46Arg	missense_variant	2/5	ENST00000250378.7	NP_001827.1
CMA1	NM_001308083.2	c.-125+749G>C		intron_variant			NP_001295012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CMA1	ENST00000250378.7	c.136G>C	p.Gly46Arg	missense_variant	2/5	1	NM_001836.5	ENSP00000250378	P1
CMA1	ENST00000206446.4	c.-125+749G>C		intron_variant		1		ENSP00000206446
	ENST00000555109.1	n.144-705C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00385 AC: 586 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00867

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00526

Gnomad OTH AF: 0.00814

GnomAD3 exomes AF: 0.00459 AC: 1154 AN: 251240 Hom.: 5 AF XY: 0.00478 AC XY: 649 AN XY: 135768

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00844

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00252

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.00547

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00411 AC: 6006 AN: 1461880 Hom.: 20 Cov.: 31 AF XY: 0.00424 AC XY: 3080 AN XY: 727240

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00306

Gnomad4 ASJ exome AF: 0.00849

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00323

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.00399

Gnomad4 OTH exome AF: 0.00402

GnomAD4 genome AF: 0.00384 AC: 585 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00402 AC XY: 299 AN XY: 74450

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00867

Gnomad4 NFE AF: 0.00525

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00457 Hom.: 1

Bravo AF: 0.00342

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00451 AC: 547

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00649

EpiControl AF: 0.00765

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 28, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.94
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.15
Sift	Uncertain	0.022	D
Sift4G	Benign	0.12	T
Polyphen		0.96	D
Vest4		0.28
MVP		0.75
MPC		0.0037
ClinPred		0.069	T
GERP RS		-1.2
Varity_R		0.45
gMVP		0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs5246; hg19: chr14-24976635;