rs397508229

Positions:

• chr7-117578327-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_000492.4(CFTR):​c.1585-9412A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: -0.494

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117578327-A-G is Pathogenic according to our data. Variant chr7-117578327-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53284.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, not_provided=1, Uncertain_significance=1, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1585-9412A>G		intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1585-9412A>G		intron_variant		1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152080 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74290

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:4 Uncertain:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 26, 2018	The c.1585-9412A>G intronic pathogenic mutation results from an A to G substitution 9412 nucleotides upstream from coding exon 12 in the CFTR gene. This mutation (reported as c.1584+18672A>G) has been detected in multiple individuals affected with cystic fibrosis who have a pathogenic mutation on the other chromosome (Costantino L et al. Am. J. Respir. Cell Mol. Biol., 2013 May;48:619-25). In addition, this mutation has been shown to activate two out-of-frame pseudoexons (104 and 65 base pairs) by creating a splice donor site (Costantino L et al. J. Cyst. Fibros., 2010 Dec;9:411-8; Costantino L et al. Am. J. Respir. Cell Mol. Biol., 2013 May;48:619-25; Felício V et al. Clin. Genet., 2017 03;91:476-481). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2023	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 53284). This variant has been observed in individuals with cystic fibrosis (PMID: 20875776, 23349053). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 11 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 20, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 10, 2023	This intronic CFTR variant has been identified in multiple individuals with features of cystic fibrosis who carry a second CF-causing variant. This variant (rs397508229) is rare (<0.1%) in a large population dataset (gnomAD: 1/152080 total alleles; 0.0006575%; no homozygotes) and has been reported in ClinVar (Variation ID: 53284). Functional studies demonstrate that this deep intronic variant creates a cryptic splice donor site that leads to aberrant splicing. We consider CFTR c.1585-9412A>G to be likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	21
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.68		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.68		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508229; hg19: chr7-117218381;