rs185028612

Variant names:

• chr7-117479634-A-G
• rs185028612
• ENST00000546407.1:n.166+3826A>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_Strong BP6

The ENST00000446805(CFTR):​c.-251A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 204,702 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (1 hom.)
• Consequence: CFTR ENST00000446805 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -1.10

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-117479634-A-G is Benign according to our data. Variant chr7-117479634-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 189027.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=6}.

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+3826A>G		intron_variant	Intron 2 of 2	1
CFTR	ENST00000446805	c.-251A>G		5_prime_UTR_variant	Exon 3 of 6	4		ENSP00000417012.1
CFTR	ENST00000673785.1	c.-406+13803A>G		intron_variant	Intron 3 of 12			ENSP00000501235.1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 284 AN: 152046 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00962

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00239

GnomAD4 exome AF: 0.00192 AC: 101 AN: 52538 Hom.: 1 Cov.: 0 AF XY: 0.00182 AC XY: 50 AN XY: 27450

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00864

Gnomad4 NFE exome AF: 0.00254

Gnomad4 OTH exome AF: 0.00178

GnomAD4 genome AF: 0.00187 AC: 284 AN: 152164 Hom.: 1 Cov.: 32 AF XY: 0.00212 AC XY: 158 AN XY: 74390

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00962

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00408 Hom.: 1

Bravo AF: 0.00116

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 10, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2025	CFTR: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 19, 2024	- -

Cystic fibrosis Benign:2

Likely benign, criteria provided, single submitter	literature only	Counsyl	Oct 24, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2024	- -

CFTR-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 04, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary pancreatitis Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Jun 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.47

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs185028612; hg19: chr7-117119688;