7-117589476-G-T

Variant names:

• chr7-117589476-G-T
• rs397508261
• NM_000492.4:c.1680-877G>T

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS3 PM2 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1680-877G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000696867: The variant was reported in the literature in compound heterozygous and homozygous individuals affected with Cystic Fibrosis (Lee_2017). The variant was absent in 31352 control chromosomes (gnomAD). c.1680-877G>T has been reported in the literature in compound heterozygous and homozygous individuals affected with Cystic Fibrosis (Lee_2017). Internal structural analysis indicates that this variant affects mRNA splicing and this variant results in creating a deep intronic donor and the inclusion of a 53 bp pseudoexon between exons 12 and 13 in the final processed mRNA (p.Ala561Serfs*15) (Lee_2017). Lee_2017 Functional studies in the literature report that this variant affects mRNA splicing and results in the creation of a deep intronic donor and the inclusion of a 53 bp pseudoexon between exons 12 and 13 in the final processed mRNA (p.Ala561Serfs*15). PMID:28728842 "Functional studies in the literature report that this variant affects mRNA splicing and results in the creation of a deep intronic donor and the inclusion of a 53 bp pseudoexon between exons 12 and 13 in the final processed mRNA (p.Ala561Serfs*15). PMID:28728842"; SCV001574927: Studies have shown that this variant alters CFTR gene expression (PMID:28475858).; SCV002712835: minigene bearing this alteration showed a complete loss of CFTR protein in HEK293 cells (Lee M et al. Am. J. Hum. Genet., 2017 May;100:751-765).; SCV000888072: Experimental studies have shown that this variant activates a cryptic donor site that causes the inclusion of a 53 bp pseudo exon between exons 12 and 13 in the final CFTR mRNA and a frameshift in the coding sequence (p.Ala561Serfs*15). This results in complete loss of normal CFTR protein (PMID:28475858 (2017)).".

• Frequency: Genomes: not found (cov: 33)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: -1.23
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000696867: The variant was reported in the literature in compound heterozygous and homozygous individuals affected with Cystic Fibrosis (Lee_2017). The variant was absent in 31352 control chromosomes (gnomAD). c.1680-877G>T has been reported in the literature in compound heterozygous and homozygous individuals affected with Cystic Fibrosis (Lee_2017). Internal structural analysis indicates that this variant affects mRNA splicing and this variant results in creating a deep intronic donor and the inclusion of a 53 bp pseudoexon between exons 12 and 13 in the final processed mRNA (p.Ala561Serfs*15) (Lee_2017). Lee_2017 Functional studies in the literature report that this variant affects mRNA splicing and results in the creation of a deep intronic donor and the inclusion of a 53 bp pseudoexon between exons 12 and 13 in the final processed mRNA (p.Ala561Serfs*15). PMID:28728842 "Functional studies in the literature report that this variant affects mRNA splicing and results in the creation of a deep intronic donor and the inclusion of a 53 bp pseudoexon between exons 12 and 13 in the final processed mRNA (p.Ala561Serfs*15). PMID:28728842"; SCV001574927: Studies have shown that this variant alters CFTR gene expression (PMID: 28475858).; SCV002712835: minigene bearing this alteration showed a complete loss of CFTR protein in HEK293 cells (Lee M et al. Am. J. Hum. Genet., 2017 May;100:751-765).; SCV000888072: Experimental studies have shown that this variant activates a cryptic donor site that causes the inclusion of a 53 bp pseudo exon between exons 12 and 13 in the final CFTR mRNA and a frameshift in the coding sequence (p.Ala561Serfs*15). This results in complete loss of normal CFTR protein (PMID: 28475858 (2017)).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117589476-G-T is Pathogenic according to our data. Variant chr7-117589476-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 53331.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1680-877G>T		intron	N/A	NP_000483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1680-877G>T		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1680-877G>T		intron	N/A	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1679+1643G>T		intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Cystic fibrosis (6)
2	-	-	not provided (2)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	CFTR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	19
DANN	Benign	0.21
PhyloP100		-1.2
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.67		Position offset: -6

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

Other links and lift over

dbSNP: rs397508261; hg19: chr7-117229530;