rs397508634

Positions:

• chr7-117652864-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000492.4(CFTR):​c.3896C>T​(p.Thr1299Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,419,508 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1299T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:5 O:1
• Conservation: PhyloP100: 3.02

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain ABC transporter 2 (size 233) in uniprot entity CFTR_HUMAN there are 28 pathogenic changes around while only 3 benign (90%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 7-117652864-C-T is Pathogenic according to our data. Variant chr7-117652864-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53844.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, not_provided=1, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3896C>T	p.Thr1299Ile	missense_variant	24/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3896C>T	p.Thr1299Ile	missense_variant	24/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1419508 Hom.: 0 Cov.: 26 AF XY: 0.00000282 AC XY: 2 AN XY: 708348

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

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: 0.00000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 4 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM3_STR, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 20, 2023	Variant summary: CFTR c.3896C>T (p.Thr1299Ile) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249246 control chromosomes (gnomAD). c.3896C>T has been reported in the literature in multiple individuals affected with cystic fibrosis (e.g. Liechti-Gallati_1999, Rock_2005, Alonso_2007, Ooi_2015, Minso_2020, Gonska_2021), including patients who carried a 2nd pathogenic variant. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10439967, 16202788, 17331079, 25963003, 33020115, 34814176). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as likely pathogenic (n=1) or VUS (n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 13, 2018

The CFTR c.3896C>T; p.Thr1299Ile variant (rs397508634), is reported in the literature in individuals with a suspected diagnosis of cystic fibrosis, including with the common pathogenic F508del variant on the opposite chromosome (Alonso 2007, Liechti-Gallati 1999, Ooi 2015, Rock 2005). This variant is reported in ClinVar (Variation ID: 53844), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The threonine at codon 1299 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Thr1299Ile variant is uncertain at this time. References: Alonso MJ et al. Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. Ann Hum Genet. 2007 Mar;71(Pt 2):194-201. Liechti-Gallati S et al. Two buffer PAGE system-based SSCP/HD analysis: a general protocol for rapid and sensitive mutation screening in cystic fibrosis and any other human genetic disease. Eur J Hum Genet. 1999 Jul;7(5):590-8. Ooi CY et al. Inconclusive diagnosis of cystic fibrosis after newborn screening. Pediatrics. 2015 Jun;135(6):e1377-85. Rock MJ et al. Newborn screening for cystic fibrosis in Wisconsin: nine-year experience with routine trypsinogen/DNA testing. J Pediatr. 2005 Sep;147(3 Suppl):S73-7. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jan 14, 2021

- -

CFTR-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.4	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-4.5	D;D;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		0.97	D;.;.
Vest4		0.81
MutPred		0.96		Gain of catalytic residue at L1304 (P = 0.0375);.;.;
MVP		1.0
MPC		0.012
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.93
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397508634; hg19: chr7-117292918;