rs397508387

Variant names:

• chr7-117594930-G-T
• rs397508387
• NM_000492.4:c.2491G>T

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PVS1 PS3 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.2491G>T​(p.Glu831*) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.000013 in 1,460,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV002741026: "In vitro studies show that this alteration may result in alternative splicing (Hinzpeter A et al. PLoS Genet, 2010 Oct" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E831E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 6.70
• Publications: 54 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 24 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002741026: "In vitro studies show that this alteration may result in alternative splicing (Hinzpeter A et al. PLoS Genet, 2010 Oct;6:; Sharma N et al. PLoS Genet, 2018 11;14:e1007723)."; SCV004105954: Functional analysis indicated that this nucleotide change leads to generation of three isoforms: aberrant splicing of CFTR and an isoform with an in-frame deletion of exon 15; an isoform with a protein truncation at p.Glu831*; and an isoform harboring a single amino acid deletion of p.Glu831 (Sharma et al. 2018. PubMed ID: 30444886).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117594930-G-T is Pathogenic according to our data. Variant chr7-117594930-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 53501.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.2491G>T	p.Glu831*	stop_gained splice_region	Exon 15 of 27	NP_000483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.2491G>T	p.Glu831*	stop_gained splice_region	Exon 15 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.2491G>T	p.Glu831*	stop_gained splice_region	Exon 15 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.2404G>T	p.Glu802*	stop_gained splice_region	Exon 14 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251276 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1460614 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 10 AN XY: 726678

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111224

Other (OTH) AF: 0.0000497 AC: 3 AN: 60330

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000205 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Cystic fibrosis (7)
2	-	-	CFTR-related disorder (2)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (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	-	-	Hereditary pancreatitis (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	54
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		6.7
Vest4		0.74
GERP RS		5.3
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
Splicevardb		3.0
SpliceAI score (max)		0.56		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 3
DS_AL_spliceai		0.56		Position offset: 0

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

Other links and lift over

dbSNP: rs397508387; hg19: chr7-117234984;