7-117627758-T-G

Position:

chr7-117627758-T-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_000492.4(CFTR):c.3705T>G(p.Ser1235Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00782 in 1,611,572 control chromosomes in the GnomAD database, including 76 homozygotes. 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 0.0057 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0081 ( 71 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:5B:15

Conservation

PhyloP100: 1.63

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a domain ABC transporter 2 (size 233) in uniprot entity CFTR_HUMAN there are 28 pathogenic changes around while only 3 benign (90%) in NM_000492.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0107719).

BP6

Variant 7-117627758-T-G is Benign according to our data. Variant chr7-117627758-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35872.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Likely_pathogenic=1, Benign=7, Uncertain_significance=3}. Variant chr7-117627758-T-G is described in Lovd as [Benign]. Variant chr7-117627758-T-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3705T>G	p.Ser1235Arg	missense_variant	22/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3705T>G	p.Ser1235Arg	missense_variant	22/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.66-11418A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00566

AC:

861

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.00367

Gnomad ASJ

AF:

0.00721

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00891

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00497

AC:

1235

AN:

248242

Hom.:

AF XY:

0.00505

AC XY:

678

AN XY:

134318

show subpopulations

Gnomad AFR exome

AF:

0.00197

Gnomad AMR exome

AF:

0.00258

Gnomad ASJ exome

AF:

0.00866

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00226

Gnomad FIN exome

AF:

0.00407

Gnomad NFE exome

AF:

0.00749

Gnomad OTH exome

AF:

0.00543

GnomAD4 exome

AF:

0.00805

AC:

11749

AN:

1459304

Hom.:

Cov.:

AF XY:

0.00792

AC XY:

5747

AN XY:

726034

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.00280

Gnomad4 ASJ exome

AF:

0.00724

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00271

Gnomad4 FIN exome

AF:

0.00388

Gnomad4 NFE exome

AF:

0.00949

Gnomad4 OTH exome

AF:

0.00690

GnomAD4 genome

AF:

0.00565

AC:

861

AN:

152268

Hom.:

Cov.:

AF XY:

0.00560

AC XY:

417

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.00366

Gnomad4 ASJ

AF:

0.00721

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00456

Gnomad4 FIN

AF:

0.00377

Gnomad4 NFE

AF:

0.00891

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00757

Hom.:

Bravo

AF:

0.00526

TwinsUK

AF:

0.0108

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00494

AC:

600

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00764

EpiControl

AF:

0.00753

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:5Benign:15

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:2Benign:7

Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 29, 2013	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 11, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 26, 2019	This alteration is classified as likely 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 26, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 22, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 14, 2018	The p.Ser1235Arg variant in CFTR is classified as benign because it has been ide ntified in 0.9% (87/10124) of Ashkenazi Jewish chromosomes and 0.7% (939/125536) of European chromosomes, including 4 homozygotes, by gnomAD (http://gnomad.broa dinstitute.org). ACMG/AMP Criteria applied: BA1. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 13, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2012	- -

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	The CFTR c.3705T>G; p.Ser1235Arg variant (rs34911792) is historically considered to be mildly pathogenic due to its prevalence in patients diagnosed with mild respiratory disorders (Rene 2011) or chronic pancreatitis (Hamoir 2013, Steiner 2011, Weiss 2005). However, genotype-phenotype studies indicate that the variant is observed at similar frequencies between affected and asymptomatic individuals (LaRusch 2014, Monaghan 2000, Rene 2011, Sosnay 2013). Functional studies also indicate no defect in CFTR maturation or chloride transport activity (Sosnay 2013, Van Goor 2014). The variant is listed in ClinVar (Variation ID: 35872) and is observed in the general population at an overall frequency of 0.5% (1,409/279,632 alleles, including 4 homozygotes) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.531). Current evidence indicates that this variant, when present with a pathogenic CFTR variant on the opposite chromosome, is not associated with classic cystic fibrosis. However, it remains uncertain whether it may contribute to the clinical phenotype in individuals with milder CFTR-related disease (e.g., an isolated presentation of pancreatitis, congenital bilateral absence of the vas deferens, or mild lung disease). References: Hamoir C et al. Clinical and morphological characteristics of sporadic genetically determined pancreatitis as compared to idiopathic pancreatitis: higher risk of pancreatic cancer in CFTR variants. Digestion. 2013; 87(4):229-39. PMID: 23751316. LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014; 10(7):e1004376. PMID: 25033378. Monaghan K et al. Frequency and clinical significance of the S1235R mutation in the cystic fibrosis transmembrane conductance regulator gene: results from a collaborative study. Am J Med Genet. 2000; 95(4):361-5. PMID: 11186891. Rene C et al. p.Ser1235Arg should no longer be considered as a cystic fibrosis mutation: results from a large collaborative study. Eur J Hum Genet. 2011; 19(1):36-42. PMID: 20717170. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. PMID: 23974870. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011; 32(8):912-20. PMID: 21520337. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014; 13(1):29-36. PMID: 23891399. Weiss F et al. Complete cystic fibrosis transmembrane conductance regulator gene sequencing in patients with idiopathic chronic pancreatitis and controls. Gut. 2005; 54(10):1456-60. PMID: 15987793. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 04, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	CFTR: BS2 -

Obstructive azoospermia

Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Institute of Reproductive Genetics, University of Münster

Aug 23, 2021

- -

CFTR-related disorder

Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Oct 09, 2023

- -

Hereditary pancreatitis

Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Oct 24, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Pathogenic

0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;.;.;T;.

Eigen

Benign

-0.065

Eigen_PC

Benign

0.090

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.90

D;T;T;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

N;.;.;.;.

MutationTaster

Benign

0.95

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.050

N;.;.;N;.

REVEL

Uncertain

0.53

Sift

Benign

0.079

T;.;.;T;.

Sift4G

Benign

0.065

T;.;.;T;.

Polyphen

0.41

B;.;.;.;.

Vest4

0.58

MutPred

0.73

Gain of MoRF binding (P = 0.0168);.;.;.;.;

MVP

0.97

MPC

0.0039

ClinPred

0.020

GERP RS

4.7

Varity_R

0.42

gMVP

0.69

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

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