7-117542109-G-T

Position:

• chr7-117542109-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1209+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.90

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02070673 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.2, offset of -21, new splice context is: aatGTaaca. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117542109-G-T is Pathogenic according to our data. Variant chr7-117542109-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1209+1G>T		splice_donor_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.1209+1G>T		splice_donor_variant, intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 02, 2017	The c.1209+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 9 of the CFTR gene. This nucleotide position is highly conserved in available vertebrate species. This alteration is predicted to abolish the native donor site using the ESEfinder in silico model; however experimental evidence is not currently available. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 13, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 02, 2020	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with congenital bilateral absence of the vas deferens (PMID: 22483971). ClinVar contains an entry for this variant (Variation ID: 370916). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 9 of the CFTR gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 19, 2024	Variant summary: CFTR c.1209+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of CFTR function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249772 control chromosomes. c.1209+1G>T has been reported in the literature in at least one individual affected with Cystic Fibrosis without reported second variant (e.g. da Silva Filho_2021). This report does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32819855). ClinVar contains an entry for this variant (Variation ID: 370916). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508176; hg19: chr7-117182163;