rs4148700

chr7-117536514-A-AGATTchr7-117536514-AGATTGATT-Achr7-117536514-AGATT-Achr7-117536514-A-AGATTGATTchr7-117536514-AGATTGATTGATT-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000492.4(CFTR):c.744-9_744-6dup variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,541,332 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 25)
  • Exomes 𝑓: 0.0016 (5 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.444

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 -8 ACMG points.

• BP6: Variant 7-117536514-A-AGATT is Benign according to our data. Variant chr7-117536514-A-AGATT is described in ClinVar as [Likely_benign]. Clinvar id is 35889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.744-9_744-6dup		intron_variant		ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.744-9_744-6dup		intron_variant		1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 323 AN: 151646 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.00397

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00204

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.0000951

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00161 AC: 263 AN: 163440 Hom.: 1 AF XY: 0.00145 AC XY: 126 AN XY: 86906

Gnomad AFR exome AF: 0.00440

Gnomad AMR exome AF: 0.00328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000240

Gnomad SAS exome AF: 0.00117

Gnomad FIN exome AF: 0.000238

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00162 AC: 2255 AN: 1389568 Hom.: 5 Cov.: 23 AF XY: 0.00156 AC XY: 1073 AN XY: 687308

Gnomad4 AFR exome AF: 0.00392

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.000245

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.000405

Gnomad4 NFE exome AF: 0.00166

Gnomad4 OTH exome AF: 0.00170

GnomAD4 genome AF: 0.00216 AC: 328 AN: 151764 Hom.: 1 Cov.: 25 AF XY: 0.00218 AC XY: 162 AN XY: 74148

Gnomad4 AFR AF: 0.00408

Gnomad4 AMR AF: 0.00204

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000625

Gnomad4 FIN AF: 0.0000951

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.00378

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Benign:3

Likely benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 04, 2015	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	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 25, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2023	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1805171; hg19: chr7-117176568;