rs137854873

Positions:

• chr7-117611845-G-A
• chr7-117611845-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_000492.4(CFTR):​c.3367+37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,476,608 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (15 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0880

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]

ENSG00000083622 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-117611845-G-A is Benign according to our data. Variant chr7-117611845-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 439073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3367+37G>A		intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3367+37G>A		intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 335 AN: 151430 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000631

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00106

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00389

Gnomad OTH AF: 0.00193

GnomAD3 exomes AF: 0.00216 AC: 484 AN: 224434 Hom.: 0 AF XY: 0.00222 AC XY: 270 AN XY: 121566

Gnomad AFR exome AF: 0.000608

Gnomad AMR exome AF: 0.000994

Gnomad ASJ exome AF: 0.000518

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00115

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.00365

Gnomad OTH exome AF: 0.00159

GnomAD4 exome AF: 0.00338 AC: 4478 AN: 1325062 Hom.: 15 Cov.: 19 AF XY: 0.00329 AC XY: 2186 AN XY: 665428

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.000436

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00155

Gnomad4 FIN exome AF: 0.00201

Gnomad4 NFE exome AF: 0.00401

Gnomad4 OTH exome AF: 0.00340

GnomAD4 genome AF: 0.00221 AC: 335 AN: 151546 Hom.: 0 Cov.: 31 AF XY: 0.00195 AC XY: 144 AN XY: 74016

Gnomad4 AFR AF: 0.000629

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00188

Gnomad4 FIN AF: 0.00124

Gnomad4 NFE AF: 0.00389

Gnomad4 OTH AF: 0.00191

Alfa AF: 0.00305 Hom.: 0

Bravo AF: 0.00204

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 27, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 13, 2019	- -

Cystic fibrosis Benign:1

Benign, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

the variant does not result in CFTR-RD neither -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.85
DANN	Benign	0.28

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: rs137854873; hg19: chr7-117251899;