7-117548628-GTTTTTT-GTTTTTTTT

Position:

• chr7-117548628-GTTTTTT-GTTTTTTTT

Variant summary

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

The NM_000492.4(CFTR):​c.1210-7_1210-6dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0439 in 142,512 control chromosomes in the GnomAD database, including 184 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (184 hom., cov: 31)
  • Exomes 𝑓: 0.030 (422 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11 O:1
• Conservation: PhyloP100: 0.565

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 7-117548628-G-GTT is Benign according to our data. Variant chr7-117548628-G-GTT is described in ClinVar as [Likely_benign]. Clinvar id is 161188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0643 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1210-7_1210-6dupTT		splice_region_variant, intron_variant		ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.222-6091_222-6090dupAA		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1210-7_1210-6dupTT		splice_region_variant, intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0438 AC: 6243 AN: 142412 Hom.: 181 Cov.: 31

Gnomad AFR AF: 0.0664

Gnomad AMI AF: 0.0101

Gnomad AMR AF: 0.0225

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00275

Gnomad SAS AF: 0.0345

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.0311

Gnomad OTH AF: 0.0324

GnomAD3 exomes AF: 0.0333 AC: 6825 AN: 205052 Hom.: 93 AF XY: 0.0330 AC XY: 3693 AN XY: 111880

Gnomad AFR exome AF: 0.0700

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.00153

Gnomad SAS exome AF: 0.0248

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.0308

Gnomad OTH exome AF: 0.0305

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0299 AC: 42111 AN: 1406430 Hom.: 422 Cov.: 36 AF XY: 0.0295 AC XY: 20617 AN XY: 699778

Gnomad4 AFR exome AF: 0.0601

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.00584

Gnomad4 SAS exome AF: 0.0250

Gnomad4 FIN exome AF: 0.102

Gnomad4 NFE exome AF: 0.0282

Gnomad4 OTH exome AF: 0.0278

GnomAD4 genome AF: 0.0439 AC: 6260 AN: 142512 Hom.: 184 Cov.: 31 AF XY: 0.0473 AC XY: 3286 AN XY: 69466

Gnomad4 AFR AF: 0.0664

Gnomad4 AMR AF: 0.0225

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00276

Gnomad4 SAS AF: 0.0343

Gnomad4 FIN AF: 0.119

Gnomad4 NFE AF: 0.0311

Gnomad4 OTH AF: 0.0367

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 16, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Cystic fibrosis Benign:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	The severity of lung disease in individuals heterozygous or homozygous for p.Arg117His depends on the presence of a variation in the poly T tract of intron 9, c.1210-12T[5_9] [Massie et al 2001]. Individuals with a CF-causing variant plus the 5T variant in cis with p.Arg117His usually develop the lung disease of CF, but those individuals with p.Arg117His and the 7T variant or the 9T variant have a highly variable phenotype that can range from no symptoms to mild lung disease [Kiesewetter et al 1993, Chmiel et al 1999]. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2021	- -
Benign, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 29, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2018

Intact protein function observed by in vitro/ex vivo assays;Intronic alteration with no splicing impact by rt-pcr analysis or other splicing assay;Other strong data -

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: rs1805177; hg19: chr7-117188682;