rs4148705

Variant names:

• chr7-117548629-T-TG
• rs4148705
• NM_000492.4:c.1210-12_1210-11insG

Your query was ambiguous. Multiple possible variants found:

• chr7-117548629-T-TG
• chr7-117548629-T-TGTG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000492.4(CFTR):​c.1210-12_1210-11insG variant causes a 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 NM_000492.4 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.236
• Publications: 0 publications found

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:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1210-12_1210-11insG		intron_variant	Intron 9 of 26	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.222-6091_222-6090insC		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1210-12_1210-11insG		intron_variant	Intron 9 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 190 AN: 133130 Hom.: 2 Cov.: 32

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

GnomAD2 exomes AF: 0.000393 AC: 83 AN: 211464 AF XY: 0.000365

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 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.: 1 Cov.: 37 AF XY: 0.00108 AC XY: 731 AN XY: 676144

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000909 AC: 27 AN: 29704

American (AMR) AF: 0.00224 AC: 96 AN: 42768

Ashkenazi Jewish (ASJ) AF: 0.000297 AC: 7 AN: 23606

East Asian (EAS) AF: 0.00963 AC: 372 AN: 38644

South Asian (SAS) AF: 0.00313 AC: 260 AN: 83100

European-Finnish (FIN) AF: 0.000120 AC: 6 AN: 50168

Middle Eastern (MID) AF: 0.000728 AC: 4 AN: 5498

European-Non Finnish (NFE) AF: 0.000598 AC: 615 AN: 1028564

Other (OTH) AF: 0.00137 AC: 76 AN: 55550

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00143 AC: 190 AN: 133216 Hom.: 2 Cov.: 32 AF XY: 0.00156 AC XY: 101 AN XY: 64656

African (AFR) AF: 0.000781 AC: 27 AN: 34560

American (AMR) AF: 0.00254 AC: 36 AN: 14154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3234

East Asian (EAS) AF: 0.0133 AC: 68 AN: 5120

South Asian (SAS) AF: 0.00573 AC: 25 AN: 4360

European-Finnish (FIN) AF: 0.000128 AC: 1 AN: 7816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000541 AC: 33 AN: 60982

Other (OTH) AF: 0.00 AC: 0 AN: 1878

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:3

May 11, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2022

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2022

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder Uncertain:1

Feb 17, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs4148705; hg19: chr7-117188683;