rs199630678

Positions:

• chr7-117627505-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_000492.4(CFTR):​c.3469-17T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00085 in 1,612,446 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (4 hom.)
• Consequence: CFTR NM_000492.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7
• Conservation: PhyloP100: 2.01

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-117627505-T-C is Benign according to our data. Variant chr7-117627505-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53751.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=5}. Variant chr7-117627505-T-C is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 4 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3469-17T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3469-17T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000492.4	ENSP00000003084	P2
	ENST00000456270.1	n.66-11165A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000592 AC: 148 AN: 249920 Hom.: 1 AF XY: 0.000822 AC XY: 111 AN XY: 135080

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000337

Gnomad OTH exome AF: 0.000823

GnomAD4 exome AF: 0.000888 AC: 1297 AN: 1460162 Hom.: 4 Cov.: 31 AF XY: 0.000979 AC XY: 711 AN XY: 726376

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00355

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000843

Gnomad4 OTH exome AF: 0.000763

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74456

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000438 Hom.: 0

Bravo AF: 0.000465

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2022	Also known as c.3601-17T>C, observed in individuals with cystic fibrosis, but additional information was not provided (Audrezet et al., 1993; Soltysova et al., 2018); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 26847993, 28456595, 20021716, 10439967, 17890437, 18685558, 23503723, 25797027, 28544683, 10923036, 12815607, 34426522, 7683952) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 26, 2023	The CFTR c.3469-17T>C variant has been reported in the published literature in individuals with cystic fibrosis (PMID: 7683952 (1993), 12815607 (2003), 28544683 (2017)) and CFTR-RD, including azoospermia (PMID: 20021716 (2009), 28456595 (2017)) as well as in unaffected individuals (PMID: 17890437 (2007)). The frequency of this variant in the general population, 0.0033 (100/30538 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect CFTR mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 15, 2018	- -

Cystic fibrosis Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 03, 2022	This alteration is classified as 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 26, 2021	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 30, 2023	Variant summary: CFTR c.3469-17T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00059 in 250506 control chromosomes, predominantly at a frequency of 0.0033 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00059 vs 0.013), allowing no conclusion about variant significance. c.3469-17T>C has been reported in the literature as non-informative genotypes (second allele and/or phase not specified) in cohorts of individuals affected with Cystic Fibrosis, diffuse bronchiectasis and azoospermia (e.g. Audrezet_1993, Claustres_2000, Scotet_2003, Gallati_2009, Soltysova_2018, Vaidyanathan_2022) but it was also reported in healthy controls (e.g. Bergougnoux_2015). These report(s) do not provide unequivocal conclusions about a penetrant association of the variant with fulminant Cystic Fibrosis. The variant was found to co-occur with two other deleterious CFTR variants (c.1393-1G>A and c.5T_TG12) in at-least one specimen tested at our laboratory. The phase of this variant was not determined, however it provides supporting evidence for a benign role. 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: 7683952, 25797027, 10923036, 18685558, 20021716, 28456595, 26847993, 17890437, 12815607, 28544683, 35857025, 23503723). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as benign (n=2), likely benign (n=1), or uncertain significance (n=4). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	16
DANN	Benign	0.53

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: rs199630678; hg19: chr7-117267559;