rs213989

Positions:

• chr7-117627457-C-A
• chr7-117627457-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.3469-65C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,543,244 control chromosomes in the GnomAD database, including 29,570 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2761 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26809 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.115

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-117627457-C-A is Benign according to our data. Variant chr7-117627457-C-A is described in ClinVar as [Benign]. Clinvar id is 818096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3469-65C>A		intron_variant		ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3469-65C>A		intron_variant		1	NM_000492.4	P2
	ENST00000456270.1	n.66-11117G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27886 AN: 151914 Hom.: 2760 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.151

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0142

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.194

Gnomad NFE AF: 0.204

Gnomad OTH AF: 0.179

GnomAD4 exome AF: 0.192 AC: 267179 AN: 1391212 Hom.: 26809 AF XY: 0.193 AC XY: 134207 AN XY: 694544

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.136

Gnomad4 EAS exome AF: 0.0141

Gnomad4 SAS exome AF: 0.219

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.200

Gnomad4 OTH exome AF: 0.183

GnomAD4 genome AF: 0.184 AC: 27899 AN: 152032 Hom.: 2761 Cov.: 32 AF XY: 0.183 AC XY: 13625 AN XY: 74310

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.0141

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.233

Gnomad4 NFE AF: 0.204

Gnomad4 OTH AF: 0.177

Alfa AF: 0.202 Hom.: 526

Bravo AF: 0.174

Asia WGS AF: 0.111 AC: 386 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Benign:1

Benign, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

the variant does not result in CFTR-RD neither -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.5
DANN	Benign	0.44

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: rs213989; hg19: chr7-117267511;