rs5248

Variant names:

• chr14-24506608-T-C
• rs5248
• NM_001836.5:c.210-4A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001836.5(CMA1):​c.210-4A>G variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.7636
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 17 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
CMA1	NM_001836.5	c.210-4A>G		splice_region_variant, intron_variant	Intron 2 of 4	ENST00000250378.7	NP_001827.1
CMA1	NM_001308083.2	c.-124-4A>G		splice_region_variant, intron_variant	Intron 1 of 3		NP_001295012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CMA1	ENST00000250378.7	c.210-4A>G		splice_region_variant, intron_variant	Intron 2 of 4	1	NM_001836.5	ENSP00000250378.3
CMA1	ENST00000206446.4	c.-124-4A>G		splice_region_variant, intron_variant	Intron 1 of 3	1		ENSP00000206446.4
ENSG00000258744	ENST00000555109.2	n.552-1526T>C		intron_variant	Intron 3 of 3	5
ENSG00000258744	ENST00000816252.1	n.440-1526T>C		intron_variant	Intron 2 of 2

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

GnomAD2 exomes AF: 0.0859 AC: 21490 AN: 250260 AF XY: 0.0857

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 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

African (AFR) AF: 0.130 AC: 4336 AN: 33418

American (AMR) AF: 0.0537 AC: 2393 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.0604 AC: 1576 AN: 26096

East Asian (EAS) AF: 0.209 AC: 8292 AN: 39694

South Asian (SAS) AF: 0.0964 AC: 8312 AN: 86180

European-Finnish (FIN) AF: 0.0359 AC: 1917 AN: 53402

Middle Eastern (MID) AF: 0.112 AC: 632 AN: 5642

European-Non Finnish (NFE) AF: 0.0785 AC: 87240 AN: 1111498

Other (OTH) AF: 0.0846 AC: 5106 AN: 60342

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

African (AFR) AF: 0.125 AC: 5190 AN: 41496

American (AMR) AF: 0.0736 AC: 1125 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0615 AC: 213 AN: 3464

East Asian (EAS) AF: 0.203 AC: 1046 AN: 5162

South Asian (SAS) AF: 0.102 AC: 489 AN: 4806

European-Finnish (FIN) AF: 0.0306 AC: 325 AN: 10616

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0759 AC: 5161 AN: 67964

Other (OTH) AF: 0.0927 AC: 196 AN: 2114

Alfa AF: 0.0809 Hom.: 326

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
PhyloP100		1.9
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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