rs397508480

chr7-117610547-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000492.4(CFTR):c.3017C>A(p.Ala1006Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 U:2 O:1
• Conservation: PhyloP100: 0.171

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 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 7-117610547-C-A is Pathogenic according to our data. Variant chr7-117610547-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 53627.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610547-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3017C>A	p.Ala1006Glu	missense_variant	19/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3017C>A	p.Ala1006Glu	missense_variant	19/27	1	NM_000492.4	P2
	ENST00000456270.1	n.178-5558G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251148 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135726

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461118 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726862

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:3 Uncertain:1 Other:1

Pathogenic, reviewed by expert panel	research	CFTR2	Aug 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 09, 2017	The p.V562I variant (also known as c.1684G>A), located in coding exon 13 of the CFTR gene, results from a G to A substitution at nucleotide position 1684. The p.A1006E variant (also known as c.3017C>A), located in coding exon 19 of the CFTR gene, results from a C to A substitution at nucleotide position 3017. The (TG)11-5T variant is located in intron 9 of the CFTR gene within the poly-thymidine tract, and results in decreased efficiency of exon 10 splicing. The 5T variant in trans with a pathogenic CFTR mutation, or in the homozygous state, has been associated with CFTR-related disorders, including bronchiectasis (Sosnay et al. Pediatr Clin North Am 2016;63(4):585-98), acute recurrent or chronic pancreatitis (Werlin et al. J Pediatr Gastroenterol Nutr 2015; 60(5):675-9, Masson et al. PLoS One 2013; 8(8):e73522), and congenital bilateral absence of the vas deferens (CBAVD) (Bombieri et al. J Cyst Fibros 2011;10 Suppl 2:S86-102). The p.V562I, p.A1006E, and (TG)11-5T variants have often been seen in cis and reported as part of a complex allele [(TG)11-5T;p.V562I;p.A1006E]. This complex allele is shown to segregate with disease in two families: one comprised of a pair of sisters, the other of four siblings affected with cystic fibrosis (CF) (Tomaiuolo AC et al. Clin Invest Med, 2010 Aug;33:E234-9). In a study aimed at understanding the relationship between phenotype and genotype in cystic fibrosis, the [(TG)11-5T;p.V562I;p.A1006E] complex allele was identified in trans with a pathogenic mutation in 11 patients. The majority of these individuals had a diagnosis of classic CF with pancreatic sufficiency, although CFTR-related disorders were also reported (Lucarelli M et al. Mol. Med., 2015 Apr;21:257-75). Based on the available evidence, the [(TG)11-5T;p.V562I;p.A1006E] complex allele is classified as disease causing. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Aug 31, 2021	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 16, 2022	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1006 of the CFTR protein (p.Ala1006Glu). 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 missense change has been observed in individual(s) with clinical features of CFTR-related conditions (PMID: 7541510, 16189704, 20691141, 21858268, 25910067, 29805046). ClinVar contains an entry for this variant (Variation ID: 53627). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function. Experimental studies have shown that this missense change affects CFTR function (PMID: 29805046, 30046002). 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. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 29, 2022

Published functional studies demonstrate a damaging effect: reduced chloride channel function (Han et al., 2018; Raraigh et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.3149C>A; This variant is associated with the following publications: (PMID: 18456578, 7541510, 34996830, 21858268, 32060344, 20691141, 35032736, 30888834, 29805046, 17331079, 35698092, 15084222, 25192979, 16189704, 10875853, 30046002, 25910067, 30134826) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 16, 2021

Variant summary: CFTR c.3017C>A (p.Ala1006Glu) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251148 control chromosomes. c.3017C>A has been reported in the literature in individuals affected with Cystic Fibrosis (example, Ferec_1995, Alonso_2007, McGinniss_2005, Tomaiuolo_2010, Lucarelli_2015). In several ascertainments, we identified a co-occurrence in cis with another pathogenic variant (CFTR 5T-TG11), providing supporting evidence for a benign role. This variant has also been frequently reported in cis with p.Val562Ile and the 5T-TG11 haplotype (example, Alonso_2007, McGinniss_2005, Tomaiuolo_2010, Lucarelli_2015). However, we have not identified conclusive evidence supporting the pathogenicity of p.Val562Ile in isolation, therefore, the clinical outcome of this triple complex of 5T-TG11, p.Ala1006Glu and p.Val562Ile remains uncertain. At-least two publications report experimental evidence evaluating an impact on protein function in isolation. The most pronounced variant effect results in <10% of normal CFTR activity (example, Han_2018, Raraigh_2018). One clinical diagnostic laboratory and the CFTR2 database have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The CFTR2 database classifies the variant as classified the variant as pathogenic and the clinical diagnostic laboratory classified the variant as uncertain significance. Overlapping but not identical evidence utilized in the context of this evaluation have been cited by the clinical diagnostic laboratory submitter. Based on the evidence outlined above, the variant in isolation was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Benign	14
Dann	Benign	0.94
DEOGEN2	Pathogenic	0.91	D;.;.;D;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.5	M;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N;.;.;N;.
REVEL	Uncertain	0.58
Sift	Benign	0.036	D;.;.;D;.
Sift4G	Uncertain	0.053	T;.;.;T;.
Polyphen		0.15	B;.;.;.;.
Vest4		0.87
MutPred		0.91		Gain of helix (P = 0.1736);.;.;.;.;
MVP		0.96
MPC		0.0056
ClinPred		0.37	T
GERP RS		0.025
Varity_R		0.59
gMVP		0.96

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: rs397508480; hg19: chr7-117250601;