rs397508775

Positions:

• chr7-117535315-G-A

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.647G>A​(p.Trp216*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:6 O:1
• Conservation: PhyloP100: 7.61

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117535315-G-A is Pathogenic according to our data. Variant chr7-117535315-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 54033.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535315-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.647G>A	p.Trp216*	stop_gained	6/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.647G>A	p.Trp216*	stop_gained	6/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251440 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727226

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:3 Other:1

Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2019	The p.W216* pathogenic mutation (also known as c.647G>A), located in coding exon 6 of the CFTR gene, results from a G to A substitution at nucleotide position 647. This changes the amino acid from a tryptophan to a stop codon within coding exon 6. This mutation has been identified in individuals with congenital absence of the vas deferens and cystic fibrosis (CF), including one homozygous individual with CF (Claustres M et al. Hum. Mutat., 2000;16:143-56; Anzai C et al. J. Cyst. Fibros., 2003 Mar;2:14-8; Kammesheidt A et al. Genet. Med., 2006 Sep;8:557-62; Shen Y et al. J. Pediatr., 2016 Apr;171:269-76.e1). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not specified Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 17, 2018	Variant summary: CFTR c.647G>A (p.Trp216X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 246204 control chromosomes (gnomAD and publication). The variant, c.647G>A, has been reported in the literature in multiple individuals affected with Non-classic Cystic Fibrosis, including one homozygote (Anzai_2003, Clain_2005, Claustres_2000, Kammesheidt_2006, Shen_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 18, 2018	The CFTR c.647G>A; p.Trp216Ter variant (rs397508775), also known as c.779G>A in traditional nomenclature, is reported in the literature in a homozygous or compound heterozygous state in multiple individuals affected with cystic fibrosis (Clain 2005, Claustres 2000, Kammesheidt 2006, Shen 2016) or congenital bilateral absence of the vas deferens (Anzai 2003). This variant is reported as pathogenic by an expert panel in ClinVar (Variation ID: 54033), and is only observed on one allele in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Anzai C et al. CFTR gene mutations in Japanese individuals with congenital bilateral absence of the vas deferens. J Cyst Fibros. 2003 Mar;2(1):14-8. Clain J et al. Misprocessing of the CFTR protein leads to mild cystic fibrosis phenotype. Hum Mutat. 2005 Apr;25(4):360-71. Claustres M et al. Spectrum of CFTR mutations in cystic fibrosis and in congenital absence of the vas deferens in France. Hum Mutat. 2000;16(2):143-56. Kammesheidt A et al. Comprehensive genetic analysis of the cystic fibrosis transmembrane conductance regulator from dried blood specimens--implications for newborn screening. Genet Med. 2006 Sep;8(9):557-62. Shen Y et al. Clinical Phenotypes and Genotypic Spectrum of Cystic Fibrosis in Chinese Children. J Pediatr. 2016 Apr;171:269-76.e1. -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.88
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397508775; hg19: chr7-117175369;