rs4727853

Positions:

• chr7-117548682-C-A
• chr7-117548682-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_000492.4(CFTR):​c.1251C>A​(p.Asn417Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N417S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: -0.0730

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:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004736215).
• BP6: Variant 7-117548682-C-A is Benign according to our data. Variant chr7-117548682-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193592.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=4, Uncertain_significance=3}. Variant chr7-117548682-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1251C>A	p.Asn417Lys	missense_variant	10/27	ENST00000003084.11
CFTR-AS1	NR_149084.1	n.222-6143G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1251C>A	p.Asn417Lys	missense_variant	10/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1754 AN: 85878 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.00709

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.0106

Gnomad EAS AF: 0.0190

Gnomad SAS AF: 0.0206

Gnomad FIN AF: 0.0665

Gnomad MID AF: 0.0634

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0276

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00117 AC: 1287 AN: 1104044 Hom.: 0 Cov.: 38 AF XY: 0.00117 AC XY: 647 AN XY: 554234

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00160

Gnomad4 ASJ exome AF: 0.00187

Gnomad4 EAS exome AF: 0.00194

Gnomad4 SAS exome AF: 0.00143

Gnomad4 FIN exome AF: 0.00350

Gnomad4 NFE exome AF: 0.000931

Gnomad4 OTH exome AF: 0.00170

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0204 AC: 1750 AN: 85950 Hom.: 0 Cov.: 31 AF XY: 0.0230 AC XY: 965 AN XY: 42044

Gnomad4 AFR AF: 0.0168

Gnomad4 AMR AF: 0.0241

Gnomad4 ASJ AF: 0.0106

Gnomad4 EAS AF: 0.0191

Gnomad4 SAS AF: 0.0202

Gnomad4 FIN AF: 0.0665

Gnomad4 NFE AF: 0.0159

Gnomad4 OTH AF: 0.0273

Alfa AF: 0.0901 Hom.: 0

ExAC AF: 0.0193 AC: 2338

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 30, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2017	Variant summary: The CFTR c.1251C>A (p.Asn417Lys) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant was found in 5925/206340 control chromosomes (gnomAD) at a frequency of 0.02871, which is approximately 1.5 times the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603), suggesting this variant is likely a benign polymorphism. However, gnomAD notes that the variant is located in a "segmental duplication region, failed random forests filters, and has an inbreeding coefficient of < -0.03." ExAC, 1790/94952 (frequency: 0.01885) notes that this variant is only covered in 47476 individuals (adjusted allele number = 94952), which is fewer than 80% of the individuals in ExAC, indicating a potentially low-quality site. In addition, each control database, gnomAD and ExAC, show significantly different allele frequencies in each of the subpopulations, making interpretation of the data difficult. Additionally, the relatively high allele frequencies reported by ExAC and gnomAD would be expected to result in homozygous individuals in the population if the allele is benign; however, neither database reports any homozygotes, despite allele frequencies as high as 9-12% in some subpopulations. This may be due to linkage to a nearby pathogenic variant, such as deltaF508, where homozygosity of the variant of interest results in homozygosity of the pathogenic allele, leading to a absence of homozygotes for the variant in the general population. The variant has been reported in the literature without strong evidence for or against causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign or benign. Taken together, this variant is classified as a "Variant of Uncertain Significance - Possibly Benign," until additional information becomes available such as higher quality control data and/or functional studies. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 28, 2015	- -

Cystic fibrosis Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 26, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.N417K in CFTR (NM_000492.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. Although the variant is present at 0.5826% in gnomAD Exomes, it has the flag "Failed Random Forest" and may not represent the true population frequency. The p.N417K variant is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between asparagine and lysine. The p.N417K missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The nucleotide c.1251 in CFTR is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Mar 21, 2015

- -

CFTR-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	0.0069	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	0.41
DANN	Benign	0.23
DEOGEN2	Benign	0.30	T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.68	T;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.49	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.33	N;N
REVEL	Uncertain	0.39
Sift	Benign	0.51	T;T
Sift4G	Benign	0.91	T;T
Polyphen		0.0	B;.
Vest4		0.24
MutPred		0.43		Gain of ubiquitination at N417 (P = 0.017);.;
MPC		0.0038
ClinPred		0.0033	T
GERP RS		-4.1
Varity_R		0.18
gMVP		0.47

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: rs4727853; hg19: chr7-117188736; COSMIC: COSV50040523;