rs34911792

chr7-117627758-T-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:5 B:14
• Conservation: PhyloP100: 1.63

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain 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: {Benign=6, Likely_benign=5, Uncertain_significance=3, Likely_pathogenic=1}. 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 GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3705T>G	p.Ser1235Arg	missense_variant	22/27	ENST00000003084.11

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00566 AC: 861 AN: 152150 Hom.: 5 Cov.: 32

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.: 4 AF XY: 0.00505 AC XY: 678 AN XY: 134318

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.: 71 Cov.: 32 AF XY: 0.00792 AC XY: 5747 AN XY: 726034

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.: 5 Cov.: 32 AF XY: 0.00560 AC XY: 417 AN XY: 74448

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.: 6

Bravo AF: 0.00526

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00494 AC: 600

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.00764

EpiControl AF: 0.00753

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:5 Benign:14

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:2 Benign:7

Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 22, 2020	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 11, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 29, 2013	- -
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	- -
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. -
Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -

not specified Benign:4

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 24, 2012	- -
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. -
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. -

not provided Uncertain:1 Benign: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	Jan 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 disorders 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	T
BayesDel_noAF	Pathogenic	0.32
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.;.;T;.
Eigen	Benign	-0.065
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;T;T;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.011	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;.;.;.;.
MutationTaster	Benign	0.95	D;D
PrimateAI	Uncertain	0.59	T
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	T
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

Other links and lift over

dbSNP: rs34911792; hg19: chr7-117267812; COSMIC: COSV50068708;