rs397508243

Positions:

• chr7-117504364-G-A
• chr7-117504364-G-C
• chr7-117504364-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.164+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000163 in 1,223,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: CFTR NM_000492.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 7.71

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.024758046 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117504364-G-A is Pathogenic according to our data. Variant chr7-117504364-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 53303.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117504364-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.164+1G>A		splice_donor_variant, intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.164+1G>A		splice_donor_variant, intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000163 AC: 2 AN: 1223538 Hom.: 0 Cov.: 19 AF XY: 0.00000161 AC XY: 1 AN XY: 621032

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000112

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 15, 2024	Variant summary: CFTR c.164+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. Several publications report experimental evidence that this variant affects mRNA splicing (e.g., Castellani_2008, Joynt_2020). The variant was absent in 249608 control chromosomes (gnomAD). c.164+1G>A has been reported in the literature in individuals affected with Cystic Fibrosis (e.g., Walkowiak_2001, Krenkova_2012, Kalelkar_2022). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18456578, 33085659, 34957709, 23276700, 11589722). ClinVar contains an entry for this variant (Variation ID: 53303). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 07, 2019	- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		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: rs397508243; hg19: chr7-117144418;