rs193922520

Positions:

• chr7-117627775-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.3717+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:7 U:1
• Conservation: PhyloP100: 8.61

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.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117627775-G-A is Pathogenic according to our data. Variant chr7-117627775-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 35875.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117627775-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3717+5G>A		splice_donor_5th_base_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.3717+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_000492.4	ENSP00000003084	P2
	ENST00000456270.1	n.66-11435C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246164 Hom.: 0 AF XY: 0.00000750 AC XY: 1 AN XY: 133364

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457464 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725184

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:4 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 02, 2022	The c.3717+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 22 in the CFTR gene. This variant was detected as homozygous in an individual with classic cystic fibrosis (Kilin&ccedil; MO et al. Am J Med Genet, 2002 Dec;113:250-7). In addition, this variant has <10% of wild type quantity in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 09/01/2022). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient 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, PP4 -
Pathogenic, reviewed by expert panel	research	CFTR2	Dec 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2022	Variant summary: CFTR c.3717+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing as resulting in a shortened transcript, although the primary data are not provided (example, Joynt_2020). The variant allele was found at a frequency of 4.1e-06 in 246164 control chromosomes. c.3717+5G>A has been reported in the literature as a homozygous genotype in at-least one individual and with limited genotype information in multiple individuals affected with Cystic Fibrosis (e.g. Bonyadi_2017, Bustami_2018, Kilinc_2002. These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory and an expert panel (CFTR-2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 27, 2022	This variant is also known as 3849+5G>A. This variant has been observed in individual(s) with cystic fibrosis (PMID: 12439892, 23974870). This variant is present in population databases (rs193922520, gnomAD 0.003%). This sequence change falls in intron 22 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. It affects a nucleotide within the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 35875). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 19, 2022

- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2024

The CFTR c.3717+5G>A variant is predicted to interfere with splicing. This variant, also known as c.3849+5G>A, has been reported in multiple individuals with cystic fibrosis and pancreatic insufficiency (http://www.cftr2.org; Kilinc et al. 2002. PubMed ID: 12439892). It has also been reported in an individual with unilateral congenital absence of the vas deferens (Akinsal et al. 2018. PubMed ID: 29484681) and reported as a lower risk variant for patients with cystic fibrosis to develop cystic fibrosis-related diabetes (CFRD) (Adler et al. 2008 PMID:18535191). Of note, another variant impacting the same splice site (c.3717+5G>T) has been reported together with delta508 in a patient with severe presentation (Aalbers et al. 2022. PubMed ID: 35110005). Functional assays in patient-derived intestinal organoids showed minimum swelling supporting loss of function (Aalbers et al. 2022. PubMed ID: 35110005). The c.3717+5G>A variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jarganathan et al. 2019. PubMed ID: 30661751) and has been confirmed to cause abnormal splicing, resulting in a truncated protein (Joynt et al. 2020. PMID: 33085659). It is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD and is interpreted as pathogenic by the CFTR2 expert group in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/35875/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Benign	0.79
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.21	T;T
MetaRNN	Pathogenic	0.88	D;D
MutationTaster	Benign	1.0	D;D
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.56		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193922520; hg19: chr7-117267829;