chr7-117559587-A-G

Position:

chr7-117559587-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4BP6

The NM_000492.4(CFTR):c.1516A>G(p.Ile506Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,612,486 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:10

Conservation

PhyloP100: 8.79

Variant links:

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]

CFTR links:

CFTR-AS1 (HGNC:):

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37776813).

BP6

Variant 7-117559587-A-G is Benign according to our data. Variant chr7-117559587-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7131.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=5}. Variant chr7-117559587-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1516A>G	p.Ile506Val	missense_variant	11/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730
CFTR-AS1	NR_149084.1 linkuse as main transcript	n.221+1146T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1516A>G	p.Ile506Val	missense_variant	11/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000342

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000368

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000366

AC:

AN:

251282

Hom.:

AF XY:

0.000361

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000493

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.000274

AC:

400

AN:

1460328

Hom.:

Cov.:

AF XY:

0.000288

AC XY:

209

AN XY:

726550

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00112

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000264

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.000342

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000437

Hom.:

Bravo

AF:

0.000559

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 20, 2023	The CFTR c.1516A>G; p.Ile506Val variant (rs1800091) is reported in the literature in at least two individuals with a severe pathogenic variant on the opposite allele and no symptoms of cystic fibrosis (Kobayashi 1990). The p.Ile506Val variant is reported in ClinVar (Variation ID: 7131), and is found in the general population with an overall allele frequency of 0.036% (101/282,660 alleles) in the Genome Aggregation Database. The isoleucine at codon 506 highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.57). Additionally, other amino acid substitutions at this codon (Leu, Met, Ser, Thr) have been reported in individuals with cystic fibrosis (Castellani 2008, Chevalier-Porst 1994, Deufel 1994, Strandvik 2001). While this variant is unlikely to be associated with classic cystic fibrosis, since an association with CFTR- related disorder cannot be excluded p.Ile506Val is classified as a variant of uncertain clinical significance. References: Castellani C et al. Consensus on the use and interpretation of cystic fibrosis mutation analysis in clinical practice. J Cyst Fibros. 2008 May;7(3):179-96. PMID: 18456578 Chevalier-Porst F et al. Mutation analysis in 600 French cystic fibrosis patients. J Med Genet. 1994 Jul;31(7):541-4. PMID: 7525963 Deufel A et al. Three novel mutations (I506S, S466X, 1651A-->T) in exon 10 of the cystic fibrosis transmembrane conductance regulator (CFTR) detected in patients of southern German descent. Hum Mutat. 1994;3(1):64-6. PMID: 7509683 Kobayashi K et al. Benign missense variations in the cystic fibrosis gene. Am J Hum Genet. 1990 47(4):611-5. PMID: 1977306 Strandvik B et al. Spectrum of mutations in the CFTR gene of patients with classical and atypical forms of cystic fibrosis from southwestern Sweden: identification of 12 novel mutations. Genet Test. 2001 5(3):235-42. PMID: 11788090 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 15, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27131402, 19914443, 33260873, 1977306, 32026723, 19324992, 19359498, 22975760) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CFTR: PM5 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cystic fibrosis

Uncertain:2Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 12, 2015	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	Jan 28, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, no assertion criteria provided	literature only	OMIM	Oct 01, 1990	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 06, 2016	- -

Hereditary pancreatitis

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Apr 28, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.67

D;.;.;D;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

1.0

L;.;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.73

N;.;.;N;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.0040

D;.;.;D;.

Sift4G

Uncertain

0.059

T;.;.;T;.

Polyphen

0.99

D;.;.;.;.

Vest4

0.70

MVP

1.0

MPC

0.010

ClinPred

0.067

GERP RS

5.5

Varity_R

0.74

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over