Variant chr7-117548629-T-TG details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000003084.11(CFTR):c.1210-12_1210-11insG variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 133,216 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0014 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

CFTR
ENST00000003084.11 splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.236

Variant links:

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 links:

CFTR-AS1 (HGNC:):

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1210-12_1210-11insG		splice_polypyrimidine_tract_variant, intron_variant		ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1 linkuse as main transcript	n.222-6091_222-6090insC		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1210-12_1210-11insG		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

190

AN:

133130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000784

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0133

Gnomad SAS

AF:

0.00572

Gnomad FIN

AF:

0.000128

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000541

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000393

AC:

AN:

211464

Hom.:

AF XY:

0.000365

AC XY:

AN XY:

114970

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.000223

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00348

Gnomad SAS exome

AF:

0.000216

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000321

Gnomad OTH exome

AF:

0.000394

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00108

AC:

1463

AN:

1357602

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

731

AN XY:

676144

show subpopulations

Gnomad4 AFR exome

AF:

0.000909

Gnomad4 AMR exome

AF:

0.00224

Gnomad4 ASJ exome

AF:

0.000297

Gnomad4 EAS exome

AF:

0.00963

Gnomad4 SAS exome

AF:

0.00313

Gnomad4 FIN exome

AF:

0.000120

Gnomad4 NFE exome

AF:

0.000598

Gnomad4 OTH exome

AF:

0.00137

GnomAD4 genome

AF:

0.00143

AC:

190

AN:

133216

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

101

AN XY:

64656

show subpopulations

Gnomad4 AFR

AF:

0.000781

Gnomad4 AMR

AF:

0.00254

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0133

Gnomad4 SAS

AF:

0.00573

Gnomad4 FIN

AF:

0.000128

Gnomad4 NFE

AF:

0.000541

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 11, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

CFTR-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2023

The CFTR c.1210-12_1210-11insG variant is predicted to result in an in-frame amino acid insertion (Intronic). Analysis of CFTR poly T and TG tracts indicates that this individual has a 6T/12TG allele (c.1210-34TG[12]T[6]) and a 7T/12TG allele. In the CFTR gene, poly T and TG tract alleles (5T/7T/9T and 10TG/11TG/12TG) are common polymorphic variants. Shorter poly T tracts (such as 5T) combined with longer adjacent poly TG tracts in cis (such as 12TG or 13TG) are known to decrease the efficiency of intron 8 splicing (Cuppens et al. 1998. PubMed ID: 9435322), leading to increased levels of transcripts missing exon 9 which leads to a protein with no chloride channel activity (Delaney et al. 1993. PubMed ID: 7691356; Strong et al. 1993. PubMed ID: 7684641). A poly T tract length of 6 adjacent to TG tract lengths of 11 or 12 (i.e. 6T/11TG and 6T/12TG alleles) have been documented at allele frequencies of up to ~1.5% in Asian populations (Huang et al. 2008. PubMed ID: 18350634; Jin et al. 2012. PubMed ID: 23092102) and have been reported in patients affected with CFTR-related conditions including bronchiectasis, asthma, and chronic bronchitis (Lee et al. 2003. PubMed ID: 12952861; Wang et al. 2012. PubMed ID: 23554779; Dahl et al. 2005. PubMed ID: 16212675; Kim et al. 2010. PubMed ID: 20879059). However, 6T/11TG and 6T/12TG alleles have also been documented in healthy controls (Fujiki et al. 2004. PubMed ID: 15121783; Wang et al. 2012. PubMed ID: 23554779; Chang et al. 2007. PubMed ID: 17539902; Kim et al. 2010. PubMed ID: 20879059). A 6T/13TG allele has been documented in trans with a pathogenic variant in patients with congenital bilateral absence of the vas deferens (Dayangaç et al. 2004. PubMed ID: 15070876; Viel et al. 2005. PubMed ID: 15562283). At this time, the clinical significance of the CFTR 6T/12TG allele identified in this patient is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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