7-117548606-ATGTGTGTG-ATGTGTG

Position:

• chr7-117548606-ATGTGTGTG-ATGTGTG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.1210-13_1210-12delGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,335,714 control chromosomes in the GnomAD database, including 17,978 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.26 (5655 hom., cov: 0)
  • Exomes 𝑓: 0.20 (12323 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0750

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 7-117548606-ATG-A is Benign according to our data. Variant chr7-117548606-ATG-A is described in ClinVar as [Likely_benign]. Clinvar id is 439475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1210-13_1210-12delGT		intron_variant		ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.222-6069_222-6068delCA		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1210-13_1210-12delGT		intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.256 AC: 36639 AN: 143230 Hom.: 5641 Cov.: 0

Gnomad AFR AF: 0.459

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.00103

Gnomad SAS AF: 0.109

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.236

GnomAD3 exomes AF: 0.222 AC: 39472 AN: 177682 Hom.: 2273 AF XY: 0.225 AC XY: 21551 AN XY: 95626

Gnomad AFR exome AF: 0.438

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.0237

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.260

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.205 AC: 244096 AN: 1192382 Hom.: 12323 AF XY: 0.204 AC XY: 120680 AN XY: 591510

Gnomad4 AFR exome AF: 0.422

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.150

Gnomad4 EAS exome AF: 0.0186

Gnomad4 SAS exome AF: 0.149

Gnomad4 FIN exome AF: 0.250

Gnomad4 NFE exome AF: 0.210

Gnomad4 OTH exome AF: 0.205

GnomAD4 genome AF: 0.256 AC: 36691 AN: 143332 Hom.: 5655 Cov.: 0 AF XY: 0.252 AC XY: 17562 AN XY: 69656

Gnomad4 AFR AF: 0.459

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.103

Gnomad4 EAS AF: 0.00103

Gnomad4 SAS AF: 0.108

Gnomad4 FIN AF: 0.250

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.233

Bravo AF: 0.251

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 29, 2015	c.1210-14_1210-13delTG in intron 9 of CFTR: This variant is not expected to have clinical significance because it has been identified in 47% (582/3375) of Afric an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs3832534). -
Benign, flagged submission	clinical testing	GeneDx	Mar 17, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Cystic fibrosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2021	- -
Benign, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2017	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 11, 2018

Other strong data -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
La Branchor		0.64
BranchPoint Hunter		2.0

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: rs3832534; hg19: chr7-117188660;