rs1800135

chr7-117666937-C-Achr7-117666937-C-Gchr7-117666937-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000492.4(CFTR):c.4272C>A(p.Tyr1424Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y1424Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -2.86

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 21 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117666937-C-A is Pathogenic according to our data. Variant chr7-117666937-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.4272C>A	p.Tyr1424Ter	stop_gained	27/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.4272C>A	p.Tyr1424Ter	stop_gained	27/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 20, 2019	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the CFTR protein. Other variant(s) that disrupt this region (p.Ser1455*) have been determined to be pathogenic (PMID: 17662673, 23276700, 25304080, 24388274, 27728908). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 555210). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the CFTR gene (p.Tyr1424*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 57 amino acids of the CFTR protein. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Nov 30, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Uncertain	24
Dann	Benign	0.95
Eigen	Benign	-0.77
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
MutationTaster	Benign	1.0	D;D
Vest4		0.88
GERP RS		-9.6

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs1800135; hg19: chr7-117306991;