rs397508506

Variant names:

• chr7-117611580-G-A
• rs397508506
• NM_000492.4:c.3140-1G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.3140-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,421,404 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.94
• 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: 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)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05131668 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117611580-G-A is Pathogenic according to our data. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117611580-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3140-1G>A		splice_acceptor_variant, intron_variant	Intron 19 of 26	ENST00000003084.11	NP_000483.3
CFTR-AS2	NR_199597.1	n.177+4649C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3140-1G>A		splice_acceptor_variant, intron_variant	Intron 19 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249206 AF XY: 0.00000743

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: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1421404 Hom.: 0 Cov.: 27 AF XY: 0.00000141 AC XY: 1 AN XY: 709724

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32678

American (AMR) AF: 0.00 AC: 0 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25858

East Asian (EAS) AF: 0.00 AC: 0 AN: 39466

South Asian (SAS) AF: 0.00 AC: 0 AN: 85264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075654

Other (OTH) AF: 0.00 AC: 0 AN: 59052

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:2

Dec 28, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 29, 2016

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3140-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 20 of the CFTR gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native acceptor splice site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Nov 30, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		9.9
GERP RS		5.7
PromoterAI		0.0090	Neutral
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.36		Position offset: 5
DS_AL_spliceai		0.97		Position offset: 1

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

Other links and lift over

dbSNP: rs397508506; hg19: chr7-117251634;