7-117534363-G-T

Variant names:

• chr7-117534363-G-T
• rs397508759
• NM_000492.4:c.577G>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PVS1 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):​c.577G>T​(p.Glu193*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000592 in 1,350,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000059 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9961
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 6.93
• Publications: 52 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• 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 17 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 7-117534363-G-T is Pathogenic according to our data. Variant chr7-117534363-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 54007.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.577G>T	p.Glu193*	stop_gained splice_region	Exon 5 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.577G>T	p.Glu193*	stop_gained splice_region	Exon 5 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.577G>T	p.Glu193*	stop_gained splice_region	Exon 5 of 27	ENSP00000514471.1
	CFTR	ENST00000889206.1		c.577G>T	p.Glu193*	stop_gained splice_region	Exon 5 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000592 AC: 8 AN: 1350814 Hom.: 0 Cov.: 22 AF XY: 0.00000737 AC XY: 5 AN XY: 678696

African (AFR) AF: 0.00 AC: 0 AN: 31222

American (AMR) AF: 0.00 AC: 0 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25412

East Asian (EAS) AF: 0.00 AC: 0 AN: 39122

South Asian (SAS) AF: 0.00 AC: 0 AN: 83996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5552

European-Non Finnish (NFE) AF: 0.00000791 AC: 8 AN: 1011570

Other (OTH) AF: 0.00 AC: 0 AN: 56748

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000179 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Cystic fibrosis (6)
2	-	-	not provided (2)
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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.9
Vest4		0.96
GERP RS		5.5
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.81
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

Other links and lift over

dbSNP: rs397508759; hg19: chr7-117174417;