rs1800130

Variant names:

• chr7-117642590-A-G
• rs1800130
• NM_000492.4:c.3870A>G

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.3870A>G​(p.Pro1290Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0416 in 1,613,132 control chromosomes in the GnomAD database, including 2,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (601 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1618 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: -0.238

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 7-117642590-A-G is Benign according to our data. Variant chr7-117642590-A-G is described in ClinVar as [Benign]. Clinvar id is 93153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117642590-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.238 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3870A>G	p.Pro1290Pro	synonymous_variant	Exon 23 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3870A>G	p.Pro1290Pro	synonymous_variant	Exon 23 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0712 AC: 10828 AN: 152112 Hom.: 592 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0295

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.0522

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0341

Gnomad OTH AF: 0.0598

GnomAD3 exomes AF: 0.0483 AC: 12102 AN: 250546 Hom.: 467 AF XY: 0.0474 AC XY: 6421 AN XY: 135418

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.0278

Gnomad EAS exome AF: 0.00285

Gnomad SAS exome AF: 0.0559

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.0354

Gnomad OTH exome AF: 0.0422

GnomAD4 exome AF: 0.0385 AC: 56204 AN: 1460904 Hom.: 1618 Cov.: 32 AF XY: 0.0386 AC XY: 28068 AN XY: 726730

Gnomad4 AFR exome AF: 0.154

Gnomad4 AMR exome AF: 0.0207

Gnomad4 ASJ exome AF: 0.0304

Gnomad4 EAS exome AF: 0.00473

Gnomad4 SAS exome AF: 0.0547

Gnomad4 FIN exome AF: 0.119

Gnomad4 NFE exome AF: 0.0318

Gnomad4 OTH exome AF: 0.0406

GnomAD4 genome AF: 0.0715 AC: 10879 AN: 152228 Hom.: 601 Cov.: 33 AF XY: 0.0744 AC XY: 5541 AN XY: 74434

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.0295

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.00463

Gnomad4 SAS AF: 0.0520

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.0341

Gnomad4 OTH AF: 0.0649

Alfa AF: 0.0382 Hom.: 415

Bravo AF: 0.0663

Asia WGS AF: 0.0660 AC: 231 AN: 3478

EpiCase AF: 0.0288

EpiControl AF: 0.0278

ClinVar

Significance: Benign

Submissions summary: Benign:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Benign:6

Jan 29, 2018

CFTR-France

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

the variant does not result in CFTR-RD neither -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant was identified in 3 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: BA1, BS1 -

Aug 31, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2020

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:4

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Pro1290Pro in exon 23 of CFTR: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 15.1% (665/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1800130). -

Jul 16, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder Benign:3

Aug 31, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:3

Jun 20, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 10572229, 24631642, 25033378, 23503723, 10601093, 22483971, 26436105, 27488005, 27022295, 28456595) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hereditary pancreatitis Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	1.6
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1800130; hg19: chr7-117282644;