rs895394181

Variant names:

• chr7-117648320-A-G
• rs895394181
• NM_000492.4:c.3874-4522A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PS3 PP5 BP4

The NM_000492.4(CFTR):​c.3874-4522A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000526 in 152,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV004221694: a splicing analysis performed using cells taken from multiple individuals with cystic fibrosis has found that this variant results in aberrant splicing (PMID:30389601 (2019))." and additional evidence is available in ClinVar.

• Frequency: Genomes: 𝑓 0.000053 (0 hom., cov: 31)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:2
• Conservation: PhyloP100: -0.260
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004221694: a splicing analysis performed using cells taken from multiple individuals with cystic fibrosis has found that this variant results in aberrant splicing (PMID: 30389601 (2019)).; SCV004562671: A minigene assay found this variant affects mRNA splicing resulting in the inclusion of a 125bp pseudo-exon that is predicted to result in a premature stop codon in a majority of RNA transcripts (Bergougnoux 2019). PMID: 30389601; SCV001589605: Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30389601).; SCV002570339: Functional studies demonstrate that this deep intronic variant creates a cryptic splice site that leads to aberrant splicing.; SCV002622436: One experimental study shows that this variant disrupts mRNA splicing; however, the variant's effect on splicing is incomplete (Bergougnoux A et al. J Cyst Fibros, 2019 07;18:468-475); SCV003922695: This variant indeed affects mRNA splicing which leads to the inclusion of a 125bp pseudo-exon, predicted to result in a premature stop codon, in 76% of RNA transcripts. (Bergougnoux_2019); SCV004119590: In vitro splicing analysis indicates that this change results in inclusion of 125 bp (Bergougnoux et al. 2018. PubMed ID: 30389601).
• PP5: Variant 7-117648320-A-G is Pathogenic according to our data. Variant chr7-117648320-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 500071.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89). . Strength limited to SUPPORTING due to the PP5.

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.3874-4522A>G		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.3874-4522A>G		intron	N/A	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.3868-4522A>G		intron	N/A	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.3787-4522A>G		intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 151978 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

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

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152096 Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2 AN XY: 74340

African (AFR) AF: 0.0000723 AC: 3 AN: 41506

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000712 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
4	1	-	Cystic fibrosis (5)
4	1	-	not provided (5)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	CFTR-related disorder (1)
1	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C5924204:CFTR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.6
DANN	Benign	0.62
PhyloP100		-0.26
Mutation Taster		=36/64	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs895394181; hg19: chr7-117288374;