rs1800136

Positions:

• chr7-117667054-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000492.4(CFTR):​c.4389G>A​(p.Gln1463=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,613,520 control chromosomes in the GnomAD database, including 43,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4361 hom., cov: 32)
  • Exomes 𝑓: 0.22 (39273 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.00800

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-117667054-G-A is Benign according to our data. Variant chr7-117667054-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 93157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117667054-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.008 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.4389G>A	p.Gln1463=	synonymous_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.4389G>A	p.Gln1463=	synonymous_variant	27/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34962 AN: 151946 Hom.: 4352 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.219

GnomAD3 exomes AF: 0.216 AC: 54312 AN: 250926 Hom.: 6859 AF XY: 0.223 AC XY: 30302 AN XY: 135592

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.0183

Gnomad SAS exome AF: 0.271

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.225 AC: 328310 AN: 1461456 Hom.: 39273 Cov.: 34 AF XY: 0.226 AC XY: 164504 AN XY: 727058

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.0171

Gnomad4 SAS exome AF: 0.272

Gnomad4 FIN exome AF: 0.349

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.213

GnomAD4 genome AF: 0.230 AC: 35017 AN: 152064 Hom.: 4361 Cov.: 32 AF XY: 0.234 AC XY: 17397 AN XY: 74326

Gnomad4 AFR AF: 0.243

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.0184

Gnomad4 SAS AF: 0.242

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.235

Gnomad4 OTH AF: 0.223

Alfa AF: 0.227 Hom.: 5825

Bravo AF: 0.212

Asia WGS AF: 0.167 AC: 581 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 25, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 27, 2013	Gln1463Gln in exon 27 of CFTR: This variant does not alter an amino acid and is not in a consensus splice sequence. It was identified in 21.6% (1861/8600) of European American and 24.4% (1077/4406) of African American chromosomose from a broad population screened by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu). -

Cystic fibrosis Benign:6

Benign, no assertion criteria provided	clinical testing	Payam Genetics Center, General Welfare Department of North Khorasan Province	Mar 01, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

CFTR-related disorder Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 29, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jul 23, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 16, 2022	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary pancreatitis Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Feb 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.033
DANN	Benign	0.36

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: rs1800136; hg19: chr7-117307108; COSMIC: COSV50049554;