chr7-117536684-C-T

Position:

• chr7-117536684-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.869+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0765 in 1,604,710 control chromosomes in the GnomAD database, including 4,922 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (428 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4494 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.615

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-117536684-C-T is Benign according to our data. Variant chr7-117536684-C-T is described in ClinVar as [Benign]. Clinvar id is 93159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117536684-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.084 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.869+11C>T		intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.869+11C>T		intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0743 AC: 11291 AN: 152004 Hom.: 427 Cov.: 32

Gnomad AFR AF: 0.0627

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.0685

Gnomad ASJ AF: 0.0888

Gnomad EAS AF: 0.00346

Gnomad SAS AF: 0.0517

Gnomad FIN AF: 0.0883

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.0858

Gnomad OTH AF: 0.0872

GnomAD3 exomes AF: 0.0684 AC: 16890 AN: 246796 Hom.: 664 AF XY: 0.0699 AC XY: 9346 AN XY: 133698

Gnomad AFR exome AF: 0.0617

Gnomad AMR exome AF: 0.0459

Gnomad ASJ exome AF: 0.0960

Gnomad EAS exome AF: 0.00192

Gnomad SAS exome AF: 0.0552

Gnomad FIN exome AF: 0.0936

Gnomad NFE exome AF: 0.0832

Gnomad OTH exome AF: 0.0810

GnomAD4 exome AF: 0.0767 AC: 111477 AN: 1452588 Hom.: 4494 Cov.: 30 AF XY: 0.0770 AC XY: 55688 AN XY: 723034

Gnomad4 AFR exome AF: 0.0642

Gnomad4 AMR exome AF: 0.0480

Gnomad4 ASJ exome AF: 0.0934

Gnomad4 EAS exome AF: 0.00263

Gnomad4 SAS exome AF: 0.0571

Gnomad4 FIN exome AF: 0.0987

Gnomad4 NFE exome AF: 0.0810

Gnomad4 OTH exome AF: 0.0746

GnomAD4 genome AF: 0.0743 AC: 11301 AN: 152122 Hom.: 428 Cov.: 32 AF XY: 0.0739 AC XY: 5496 AN XY: 74384

Gnomad4 AFR AF: 0.0629

Gnomad4 AMR AF: 0.0684

Gnomad4 ASJ AF: 0.0888

Gnomad4 EAS AF: 0.00347

Gnomad4 SAS AF: 0.0517

Gnomad4 FIN AF: 0.0883

Gnomad4 NFE AF: 0.0858

Gnomad4 OTH AF: 0.0886

Alfa AF: 0.0840 Hom.: 427

Bravo AF: 0.0722

Asia WGS AF: 0.0360 AC: 127 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Benign:6

Benign, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 03, 2022	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	869+11C>T in intron 7 of CFTR: This variant is not expected to have clinical sig nificance because it is not located within the conserved splice consensus sequen ce. It has been identified in 16.3% (1400/8596) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS; dbSNP rs1800503). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2018	- -

CFTR-related disorder Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.0
DANN	Benign	0.45

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: rs1800503; hg19: chr7-117176738;