7-117548628-GTTTTTT-GTTTTT

Position:

• chr7-117548628-GTTTTTT-GTTTTT

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000492.4(CFTR):​c.1210-6del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1210-6del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.222-6090del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1210-6del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000709 AC: 10 AN: 1411052 Hom.: 0 Cov.: 36 AF XY: 0.00000712 AC XY: 5 AN XY: 702200

Gnomad4 AFR exome AF: 0.0000641

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000782

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000465

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 17, 2020

Variant summary: CFTR c.1210-12[6] (also known as 6T allele or c.1210-6delT) involves the deletion of an intronic thymine nucleotide from a poly-T tract that is adjacent to a polymorphic TG repeat motif. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.8e-05 in 247720 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant has been reported in non-CF individuals in the literature including individuals affected with bronchial asthma, chronic bronchitis, bronchiectasis, CBAVD and chronic pancreatitis (e.g. Dayangac_2004, Lee_2003, Nakano_2015, Rohlfs_2003, Viel_2005, Wang_2012) but also, in East Asian controls (e.g. Fujiki_2004, Chang_2007, Huang_2008, Jin_2012, Iso_2019). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence of clinical and functional importance becomes available. -

Cystic fibrosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 29, 2021

Also known as c.1210-6delT, IVS8 6T, IVS8 T6, 1342-12 to 1342-6 delT, 1342-6delT; referred to as the 6T allele; Observed with another variant for which phase was unknown, in patients with congenital absence of vas deferens in the published literature (Dayangac 2004, Viel 2005); Observed in the heterozygous state in individuals with bronchiectasis and chronic pancreatitis (Lee 2003, Nakano 2015); This variant is associated with the following publications: (PMID: 17539902, 18350634, 16212675, 15121783, 15070876, 23554779, 12952861, 30811104, 22191729, 15562283, 23092102, 30450785, 25492507, 20879059, 32757986) -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1805177; hg19: chr7-117188682;