7-117479930-G-A

Variant names:

• chr7-117479930-G-A
• rs145483167
• ENST00000546407.1:n.166+4122G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000446805.2(CFTR):​c.-191+236G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 734,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 29)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CFTR ENST00000446805.2 intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 0.167

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000546407.1	n.166+4122G>A		intron_variant	Intron 2 of 2	1
CFTR	ENST00000673785.1	c.-406+14099G>A		intron_variant	Intron 3 of 12			ENSP00000501235.1
CFTR	ENST00000446805.2	c.-191+236G>A		intron_variant	Intron 3 of 5	4		ENSP00000417012.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151750 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000592

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000589

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 65 AN: 583226 Hom.: 0 Cov.: 6 AF XY: 0.0000853 AC XY: 27 AN XY: 316578

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.000813

Gnomad4 ASJ exome AF: 0.000369

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000154

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000266

Gnomad4 OTH exome AF: 0.000191

GnomAD4 genome AF: 0.000105 AC: 16 AN: 151750 Hom.: 0 Cov.: 29 AF XY: 0.000108 AC XY: 8 AN XY: 74106

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000592

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2023	Published functional studies demonstrate a damaging effect as c.-165G>A increases binding of FOXI1 inducing reduced CFTR promoter activity (Lopez et al., 2011); Reported in individuals with congenital absence of the vas deferens (de Meeus et al., 1998; Lopez et al., 2011); Also known as -33G>A; This variant is associated with the following publications: (PMID: 33000223, 10200050, 21948798, 12843327, 20972246) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 19, 2018	- -

Cystic fibrosis Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 23, 2022	This variant occurs in a non-coding region of the CFTR gene. It does not change the encoded amino acid sequence of the CFTR protein. This variant is present in population databases (rs145483167, gnomAD 0.1%). This variant has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 12843327). This variant is also known as -33G>A. ClinVar contains an entry for this variant (Variation ID: 439059). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects CFTR function (PMID: 20972246). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 28, 2017	- -

CFTR-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2024

The CFTR c.-165G>A variant is located in the 5' untranslated region. This variant has been reported in a patient with congenital bilateral absence of the vas deferens and resulted in reduced CFTR transcription in vitro (described as -33G>A in Lopez et al. 2011. PubMed ID: 20972246). This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.65

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs145483167; hg19: chr7-117119984;