chr7-117559590-ATCT-A

Variant names:

• chr7-117559590-ATCT-A
• rs113993960
• NM_000492.4:c.1521_1523delCTT

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 15P and 1B. PS3 PM1 PM4_Supporting PP5_Very_Strong BS1_Supporting

The NM_000492.4(CFTR):​c.1521_1523delCTT​(p.Phe508del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,612,320 control chromosomes in the GnomAD database, including 58 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★★★). ClinVar reports functional evidence for this variant: "SCV000074347: Experimental studies have shown that this variant affects CFTR function (PMID:2475911, 23974870).; SCV000221179: PS3; SCV000741228: in vitro functional studies showed this mutation results in significantly reduced chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7).; SCV002097285: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID:30030066; 27738188) - PS3."; SCV002503785: It has been identified in a homozygous state and compound heterozygous with a second pathogenic allele in cystic fibrosis cases and segregates with disease in multiple families (PMID:8092189, 1379413, 2570460, 25910067). Additionally, a Cftr Phe508del/Phe508del mouse model lacks CFTR in the apical membrane, was chloride ion-impermeable, and displayed several abnormalities found in the human disease (PMID:7560099).; SCV002761398: Additionally, a Cftr Phe508del/Phe508del mouse model lack CFTR in the apical membrane, were chloride ion-impermeable, and displayed several abnormalities found in the human disease (PMID:7560099).; SCV004101520: Experimental studies have shown that this variant affects CFTR function Sosnay et al., 2013; Terlizzi et al., 2021.; SCV005397656: Experimental evidence shows that function of the variant protein is significantly inhibited (PMID:2475911).; SCV000889288: This variant causes a severe phenotype due to deleterious effects on CFTR protein maturation and function (PMIDs: 23974870 (2013), 25148434 (2014), 26581802 (2016)).; SCV001553614: The variant is an in-frame deletion resulting in the removal of a phenylalanine (F) residue at codon 508; the deletion of p.F508 results in a misfolded mutant protein that is prematurely degraded before it reaches the plasma membrane (Maiuri_2015_PMID:26046070).; SCV004176446: Experimental studies have shown that this variant affects CFTR function (Zeiher et al. 1995).; SCV004046363: Functional studies have demonstrated that this variant disrupts the normal function of the protein (PMID:2475911, 17873061).".

• Frequency:
  • Genomes: 𝑓 0.0079 (1 hom., cov: 32)
  • Exomes 𝑓: 0.012 (57 hom.)
• Consequence: CFTR NM_000492.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic practice guideline P:88 O:7
• Conservation: PhyloP100: 7.54
• Publications: 5952 publications found

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-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000074347: Experimental studies have shown that this variant affects CFTR function (PMID: 2475911, 23974870).; SCV000221179: PS3; SCV000741228: in vitro functional studies showed this mutation results in significantly reduced chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7).; SCV002097285: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 30030066; 27738188) - PS3."; SCV002503785: It has been identified in a homozygous state and compound heterozygous with a second pathogenic allele in cystic fibrosis cases and segregates with disease in multiple families (PMID: 8092189, 1379413, 2570460, 25910067). Additionally, a Cftr Phe508del/Phe508del mouse model lacks CFTR in the apical membrane, was chloride ion-impermeable, and displayed several abnormalities found in the human disease (PMID: 7560099).; SCV002761398: Additionally, a Cftr Phe508del/Phe508del mouse model lack CFTR in the apical membrane, were chloride ion-impermeable, and displayed several abnormalities found in the human disease (PMID: 7560099).; SCV004101520: Experimental studies have shown that this variant affects CFTR function Sosnay et al., 2013; Terlizzi et al., 2021.; SCV005397656: Experimental evidence shows that function of the variant protein is significantly inhibited (PMID: 2475911).; SCV000889288: This variant causes a severe phenotype due to deleterious effects on CFTR protein maturation and function (PMIDs: 23974870 (2013), 25148434 (2014), 26581802 (2016)).; SCV001553614: The variant is an in-frame deletion resulting in the removal of a phenylalanine (F) residue at codon 508; the deletion of p.F508 results in a misfolded mutant protein that is prematurely degraded before it reaches the plasma membrane (Maiuri_2015_PMID:26046070).; SCV004176446: Experimental studies have shown that this variant affects CFTR function (Zeiher et al. 1995).; SCV004046363: Functional studies have demonstrated that this variant disrupts the normal function of the protein (PMID: 2475911, 17873061).
• PM1: In a hotspot region, there are 19 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 25 uncertain in NM_000492.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000492.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 7-117559590-ATCT-A is Pathogenic according to our data. Variant chr7-117559590-ATCT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7105.Status of the report is practice_guideline, 4 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0124 (18037/1460114) while in subpopulation NFE AF = 0.015 (16638/1110560). AF 95% confidence interval is 0.0148. There are 57 homozygotes in GnomAdExome4. There are 8794 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1521_1523delCTT	p.Phe508del	disruptive_inframe_deletion	Exon 11 of 27	NP_000483.3
	CFTR-AS1	NR_149084.1		n.221+1140_221+1142delAGA		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1521_1523delCTT	p.Phe508del	disruptive_inframe_deletion	Exon 11 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1521_1523delCTT	p.Phe508del	disruptive_inframe_deletion	Exon 11 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1521_1523delCTT	p.Phe508del	disruptive_inframe_deletion	Exon 11 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1200 AN: 152088 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00707 AC: 1776 AN: 251256 AF XY: 0.00693

Gnomad AFR exome AF: 0.00295

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.00686

GnomAD4 exome AF: 0.0124 AC: 18037 AN: 1460114 Hom.: 57 AF XY: 0.0121 AC XY: 8794 AN XY: 726470

African (AFR) AF: 0.00230 AC: 77 AN: 33444

American (AMR) AF: 0.00396 AC: 177 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00632 AC: 165 AN: 26112

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39622

South Asian (SAS) AF: 0.00247 AC: 213 AN: 86228

European-Finnish (FIN) AF: 0.00276 AC: 147 AN: 53322

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5764

European-Non Finnish (NFE) AF: 0.0150 AC: 16638 AN: 1110560

Other (OTH) AF: 0.0101 AC: 609 AN: 60344

GnomAD4 genome AF: 0.00788 AC: 1200 AN: 152206 Hom.: 1 Cov.: 32 AF XY: 0.00722 AC XY: 537 AN XY: 74420

African (AFR) AF: 0.00260 AC: 108 AN: 41556

American (AMR) AF: 0.00373 AC: 57 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4826

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0143 AC: 972 AN: 67954

Other (OTH) AF: 0.00758 AC: 16 AN: 2110

Alfa AF: 0.00312 Hom.: 0

Bravo AF: 0.00785

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0138

EpiControl AF: 0.0123

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: practice guideline

Pathogenic	VUS	Benign	Condition
46	-	-	Cystic fibrosis (48)
19	-	-	not provided (20)
5	-	-	Hereditary pancreatitis (6)
4	-	-	CFTR-related disorder (4)
3	-	-	Bronchiectasis with or without elevated sweat chloride 1 (3)
2	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (2)
2	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (2)
1	-	-	Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
1	-	-	Cystic fibrosis diagnostic test (1)
1	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis (1)
1	-	-	Duodenal stenosis (1)
1	-	-	Obstructive azoospermia (1)
1	-	-	Recurrent pancreatitis (1)
1	-	-	See cases (1)
-	-	-	Bronchiectasis with or without elevated sweat chloride 1, modifier of (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=9/91	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs113993960; hg19: chr7-117199644; COSMIC: COSV50043929; COSMIC: COSV50043929;