rs121909016

Positions:

• chr7-117540163-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.933C>G​(p.Phe311Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 2.46

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 65 pathogenic changes around while only 10 benign (87%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• PP5: Variant 7-117540163-C-G is Pathogenic according to our data. Variant chr7-117540163-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 7153.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117540163-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.933C>G	p.Phe311Leu	missense_variant	8/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.933C>G	p.Phe311Leu	missense_variant	8/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461562 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727110

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1992	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 30, 2015	The p.F311L pathogenic mutation (also known as c.933C>G), located in coding exon 8 of the CFTR gene, results from a C to G substitution at nucleotide position 933. The phenylalanine at codon 311 is replaced by leucine, an amino acid with highly similar properties. This mutation has been reported in multiple studies in patients who have classic CF symptoms and elevated sweat chloride levels along with a second pathogenic mutation (Ferec et al. Nat Genet.1992;1(3):188-191, Jezequel et al. Clin Chem. 1995;41(6Pt1):833-5, Scotet et al. Hum Mutat.2003;22(1):105). Another study reported a patient with chronic pancreatitis who had this mutation in cis with p.V754M and deltaF508 on the other chromosome (Niel et al. Hum Mutat. 2006;27(7):716-7). Based on the supporting evidence, p.F311L is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 16, 2019	This sequence change replaces phenylalanine with leucine at codon 311 of the CFTR protein (p.Phe311Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect CFTR protein function (PMID: 29805046, 30046002). This variant has been observed in several individuals affected with cystic fibrosis (PMID: 1284639, 9459534, 7539342, 24586523). ClinVar contains an entry for this variant (Variation ID: 7153). This variant is not present in population databases (ExAC no frequency). -
Pathogenic, reviewed by expert panel	research	CFTR2	Dec 08, 2017	- -

Obstructive azoospermia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Reproductive Genetics, University of Münster

Aug 23, 2021

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;.;D;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.3	M;.;.;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.4	N;.;.;N;.
REVEL	Pathogenic	0.71
Sift	Benign	0.20	T;.;.;T;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		0.75	P;.;.;.;.
Vest4		0.95
MutPred		0.88		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);
MVP		1.0
MPC		0.0051
ClinPred		0.92	D
GERP RS		4.5
Varity_R		0.74
gMVP		0.91

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: rs121909016; hg19: chr7-117180217;