7-117614719-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000492.4(CFTR):c.3468+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,590,640 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 1 hom. )

Consequence

CFTR
NM_000492.4 splice_donor_region, intron

Scores

Splicing: ADA: 0.4986

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 2.48

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3468+6T>C		splice_donor_region_variant, intron_variant		ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3468+6T>C		splice_donor_region_variant, intron_variant		1	NM_000492.4	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.177+1510A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

250594

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135428

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000294

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.0000417

AC:

AN:

1438378

Hom.:

Cov.:

AF XY:

0.0000516

AC XY:

AN XY:

717186

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000641

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000672

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 07, 2022	This sequence change falls in intron 21 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. This variant is present in population databases (rs547442588, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with Cystic Fibrosis (PMID: 27625827, 28440306). This variant is also known as c.3600+6(T‚ÜíC). ClinVar contains an entry for this variant (Variation ID: 549991). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 27, 2023	The c.3468+6T>C intronic variant results from a T to C substitution 6 nucleotides after coding exon 21 in the CFTR gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This nucleotide position is conserved on limited sequence alignment. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this donor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Feb 19, 2020	A heterozygous splice site variation in intron 21 of the CFTR gene was detected. The observed variant c.3468+6T>C has been reported in ClinVar as variant of uncertain significance previously. The variant is found to have allele frequency of <0.1% in the gnomAD database. In summary, the variant meets our criteria to be classified as a variant of unknown significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 02, 2023

Variant summary: CFTR c.3468+6T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation 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 4.8e-05 in 250594 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (4.8e-05 vs 0.013), allowing no conclusion about variant significance. c.3468+6T>C has been reported in the literature in an individual affected with Cystic Fibrosis (examples: Ashavaid_2012, Deepak_2012). These report(s) do 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 publications have been ascertained in the context of this evaluation (PMID: 23405520, 27625827). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 11, 2022

- -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

May 09, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

Cadd

Benign

Dann

Benign

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.50

dbscSNV1_RF

Benign

0.52

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.20

Position offset: -6

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over