rs1042180

Positions:

• chr7-117668359-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.*1251C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 151,942 control chromosomes in the GnomAD database, including 4,425 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4423 hom., cov: 32)
  • Exomes 𝑓: 0.32 (2 hom.)
• Consequence: CFTR NM_000492.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.33

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 7-117668359-C-T is Benign according to our data. Variant chr7-117668359-C-T is described in ClinVar as [Benign]. Clinvar id is 358748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.*1251C>T		3_prime_UTR_variant	27/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.*1251C>T		3_prime_UTR_variant	27/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35257 AN: 151788 Hom.: 4407 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.217

GnomAD4 exome AF: 0.316 AC: 12 AN: 38 Hom.: 2 Cov.: 0 AF XY: 0.313 AC XY: 10 AN XY: 32

Gnomad4 FIN exome AF: 0.265

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.233 AC: 35322 AN: 151904 Hom.: 4423 Cov.: 32 AF XY: 0.236 AC XY: 17536 AN XY: 74216

Gnomad4 AFR AF: 0.251

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.0187

Gnomad4 SAS AF: 0.243

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.235

Gnomad4 OTH AF: 0.222

Alfa AF: 0.224 Hom.: 3941

Bravo AF: 0.215

Asia WGS AF: 0.171 AC: 595 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CFTR-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	10
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1042180; hg19: chr7-117308413;