Genetic Variant CFTR:c.3469-65C>A (chr7-117627457-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.115

Variant links:

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]

CFTR links:

ENSG00000083622 (HGNC:):

ENSG00000083622 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.3469-65C>A		intron_variant	Intron 21 of 26	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.3469-65C>A		intron_variant	Intron 21 of 26	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.184

AC:

27886

AN:

151914

Hom.:

2760

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.183

AC XY:

13625

AN XY:

74310

show subpopulations

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis

Benign:1

Jan 29, 2018

CFTR-France

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

the variant does not result in CFTR-RD neither -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over