rs121908768

chr7-117540156-CCTT-Cchr7-117540156-CCTT-CCTTCTT

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000492.4(CFTR):c.935_937del(p.Phe312del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,440 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A309A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (1 hom.)
• Consequence: CFTR NM_000492.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 7.54

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000492.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 7-117540156-CCTT-C is Pathogenic according to our data. Variant chr7-117540156-CCTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.935_937del	p.Phe312del	inframe_deletion	8/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.935_937del	p.Phe312del	inframe_deletion	8/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000757 AC: 19 AN: 251076 Hom.: 1 AF XY: 0.0000442 AC XY: 6 AN XY: 135716

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461234 Hom.: 1 AF XY: 0.0000371 AC XY: 27 AN XY: 726948

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74406

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 14, 2023	CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 31, 2022	The p.F312del pathogenic mutation (also known as c.935_937delTCT, c.933_935delCTT and deltaF311 in the literature) is located in coding exon 8 of the CFTR gene. This mutation results from an in-frame deletion of 3 nucleotides at positions 935 to 937. This results in the deletion of a phenylalanine (F) residue at codon 312, within a string of F residues (codons 310 through 312). In a meta-analysis of worldwide mutation incidence, this mutation was observed in 0.2% of all cystic fibrosis (CF) alleles, and in 2.0% of African American CF alleles (Bobadilla JL et al. Hum. Mutat. 2002;19(6):575-606). In one study, this mutation was detected in trans with p.F508del in a 2-year-old patient with growth retardation who was noted to have repeated elevated sweat chloride levels, but unremarkable lung and gastrointestinal symptoms (Meitinger T et al. Hum Mol Genet. 1993;2(12):2173-2174). Another study detected this mutation in a Hispanic CF patient, but no further clinical data was provided (Schrijver I et al. J Mol Diagn. 2005;7(2):289-299). We have observed this mutation in either the homozygous or compound heterozygous state in CF patients in our clinical cohort. In addition, our internal structural analysis revealed that F312 is a part of the transmembrane loop 5 and loss of this residue results in disruptive shift of amino acids in the loop (Zhang Z et al. Cell, 2016 Dec;167:1586-1597.e9). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 26, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 14, 2023	This variant, c.935_937del, results in the deletion of 1 amino acid(s) of the CFTR protein (p.Phe312del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs758477732, gnomAD 0.04%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with cystic fibrosis (PMID: 7509232, 9443874, 16980811, 26098992). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as deltaF311. ClinVar contains an entry for this variant (Variation ID: 48704). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 10, 2022	Variant summary: CFTR c.935_937delTCT (p.Phe312del) results in an in-frame deletion that is predicted to remove one phenylalanine from three consecutive phenylalanines, located in the first transmembrane region (IPR011527) of the encoded protein. The variant allele was found at a frequency of 7.6e-05 in 251076 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.013), allowing no conclusion about variant significance. The variant (also known as deltaF311) has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g. Meitinger_1993, Friedman_1998, Heim_2001, Watts_2012, Kharrazi_2015, Taccetti_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic (n=2) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 12, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 15, 2022	PP5, PM3, PM4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 19, 2020	The CFTR c.935_937delTCT; p.Phe312del variant (rs121908768), also known as F311del, is reported in the literature in multiple individuals affected with cystic fibrosis and has been found in affected individuals in trans to the pathogenic p.Phe508del variant (Friedman 1998, Meitinger 1993). The p.Phe312del variant is also frequently observed in African-American and Hispanic cystic fibrosis patients (Kharrazi 2015, Schrijver 2005, Sugarman 2004, Watts 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 48704) and is found in the general population with an overall allele frequency of 0.008% (19/251076 alleles, including one homozygote) in the Genome Aggregation Database. This variant deletes a highly conserved phenylalanine residue, leaving the rest of the protein in-frame. Based on available information, the p.Phe312del variant is considered to be likely pathogenic. REFERENCES Friedman K et al. Cystic fibrosis transmembrane-conductance regulator mutations among African Americans. Am J Hum Genet. 1998 62(1):195-6. Kharrazi M et al. Newborn Screening for Cystic Fibrosis in California. Pediatrics. 2015 Dec;136(6):1062-72. Meitinger T et al. In frame deletion (delta F311) within a short trinucleotide repeat of the first transmembrane region of the cystic fibrosis gene. Hum Mol Genet. 1993 2(12):2173-4. Schrijver I et al. Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum. J Mol Diagn. 2005 May;7(2):289-99. Sugarman EA et al. CFTR mutation distribution among U.S. Hispanic and African American individuals: evaluation in cystic fibrosis patient and carrier screening populations. Genet Med. 2004 Sep-Oct;6(5):392-9. Watts KD et al. Hispanic Infants with cystic fibrosis show low CFTR mutation detection rates in the Illinois newborn screening program. J Genet Couns. 2012 Oct;21(5):671-5. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 23, 2022	- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

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Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 30, 2023

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Computational scores

Source: dbNSFP v4.3

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: rs121908768; hg19: chr7-117180210;