rs139729994

chr7-117614713-G-Achr7-117614713-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):c.3468G>A(p.Leu1156=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0000124 in 1,450,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L1156L*KAY) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Pathogenic reviewed by expert panel P:12 U:2
• Conservation: PhyloP100: 6.67

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117614713-G-A is Pathogenic according to our data. Variant chr7-117614713-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 53750.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117614713-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3468G>A	p.Leu1156=	splice_region_variant, synonymous_variant	21/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3468G>A	p.Leu1156=	splice_region_variant, synonymous_variant	21/27	1	NM_000492.4	P2
	ENST00000456270.1	n.177+1516C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151970 Hom.: 0 Cov.: 31

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250770 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135530

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1450358 Hom.: 0 Cov.: 27 AF XY: 0.0000125 AC XY: 9 AN XY: 722280

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000163

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000658 AC: 1 AN: 151970 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74224

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: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12 Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:6 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 18, 2020	Variant summary: CFTR c.3468G>A (p.Leu1156Leu) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site and one predicts the variant abolishes a 5 splicing donor site. Experimental evidence supports these predictions indicating that the variant causes exon-skipping leading to premature termination and truncation of CFTR (Zielendki_1994). The variant allele was found at a frequency of 4e-06 in 250770 control chromosomes (gnomAD). c.3468G>A has been reported in the literature in compound heterozygous individuals affected with Cystic Fibrosis (e.g. Claustres_2000, Zielendki_1994) while it was also reported in homozygous individuals affected with CBAVD and pancreatitis (e.g. Claustres_2017 & CFTR-France online database). These data indicate that the variant is likely to be associated with disease. Five ClinVar submitters including an expert panel (CFTR2) (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 2021	The c.3468G>A pathogenic mutation (also known as p.L1156L) is located in coding exon 21 of the CFTR gene. This variant results from a G to A substitution at nucleotide position 3468. This nucleotide substitution does not change the amino acid at codon 1156. However, this change occurs in the last base pair of coding exon 21, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in multiple individuals with cystic fibrosis in conjunction with a pathogenic mutation in CFTR by our laboratory. In one individual, this variant was confirmed to be in trans with a pathogenic mutation. In addition, this mutation (also referred to as 3600G>A) has been reported in patients with cystic fibrosis (Claustres M et al. Hum. Mutat., 2000;16:143-56; Lim MT et al. Arch. Dis. Child., 2014 Mar;99:197-202). In an expression mini-gene assay, this mutation produced no correctly-spliced CFTR RNA and protein in HEK293 cells (The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed September 14, 2017). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 02, 2022	This sequence change affects codon 1156 of the CFTR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CFTR protein. This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with CFTR-related conditions (PMID: 10923036). ClinVar contains an entry for this variant (Variation ID: 53750). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Nov 11, 2019	Previously reported disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jun 19, 2014	- -

not provided Pathogenic:3 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 11, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2020	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 24243928, 18463704, 15619636, 12833420, 21152102, 14685937, 23457292, 23951356, 23974870, 10923036, 31036917) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2023	The CFTR c.3468G>A; p.Leu1156= variant (rs139729994) is reported in the compound heterozygous state in individuals with cystic fibrosis (see links to CF databases). However, this variant has also been reported in the homozygous state in an individual with pancreatitis, and an individual with congenital bilateral absence of vas deferens (Claustres 2017, CFTR France Database). This variant is reported in ClinVar (Variation ID: 53750). It is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is a synonymous variant located in the last nucleotide of exon 21 (exon 18 for traditional numbering), and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. Functional studies using a mini-gene assay showed this variant does not produce correctly spliced CFTR RNA and protein in HEK293 cells (CFTR2 database). Based on available information, this variant is considered to be pathogenic with varying clinical consequences. REFERENCES Link to CFTR2 database: http://cftr2.org/ Link to Cystic Fibrosis Mutation Database: http://www.genet.sickkids.on.ca/ Claustres M et al. CFTR-France, a national relational patient database for sharing genetic and phenotypic data associated with rare CFTR variants. Hum Mutat. 2017 Oct;38(10):1297-1315. PMID: 28603918. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 04, 2021	PP3, PP5, PM2, PM3_strong -

Cystic fibrosis;na:CFTR-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 11, 2020

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
Cadd	Benign	21
Dann	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.76		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs139729994; hg19: chr7-117254767;