rs5248

Positions:

• chr14-24506608-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001836.5(CMA1):​c.210-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0829 in 1,612,974 control chromosomes in the GnomAD database, including 6,185 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.091 (710 hom., cov: 32)
  • Exomes 𝑓: 0.082 (5475 hom.)
• Consequence: CMA1 NM_001836.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.7636
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CMA1	NM_001836.5	c.210-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000250378.7
CMA1	NM_001308083.2	c.-124-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CMA1	ENST00000250378.7	c.210-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001836.5	P1
CMA1	ENST00000206446.4	c.-124-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
	ENST00000555109.1	n.144-1526T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0908 AC: 13808 AN: 151996 Hom.: 710 Cov.: 32

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0737

Gnomad ASJ AF: 0.0615

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0306

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.0759

Gnomad OTH AF: 0.0932

GnomAD3 exomes AF: 0.0859 AC: 21490 AN: 250260 Hom.: 1148 AF XY: 0.0857 AC XY: 11593 AN XY: 135200

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.0525

Gnomad ASJ exome AF: 0.0585

Gnomad EAS exome AF: 0.224

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.0311

Gnomad NFE exome AF: 0.0765

Gnomad OTH exome AF: 0.0771

GnomAD4 exome AF: 0.0820 AC: 119804 AN: 1460860 Hom.: 5475 Cov.: 33 AF XY: 0.0822 AC XY: 59762 AN XY: 726724

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.0537

Gnomad4 ASJ exome AF: 0.0604

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.0964

Gnomad4 FIN exome AF: 0.0359

Gnomad4 NFE exome AF: 0.0785

Gnomad4 OTH exome AF: 0.0846

GnomAD4 genome AF: 0.0909 AC: 13832 AN: 152114 Hom.: 710 Cov.: 32 AF XY: 0.0891 AC XY: 6629 AN XY: 74376

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.0736

Gnomad4 ASJ AF: 0.0615

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.0306

Gnomad4 NFE AF: 0.0759

Gnomad4 OTH AF: 0.0927

Alfa AF: 0.0799 Hom.: 296

Bravo AF: 0.0960

Asia WGS AF: 0.155 AC: 537 AN: 3476

EpiCase AF: 0.0769

EpiControl AF: 0.0787

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	23
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.76
dbscSNV1_RF	Benign	0.25
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.96		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5248; hg19: chr14-24975814; COSMIC: COSV51625896;