rs397508272

Positions:

• chr7-117509038-T-C
• chr7-117509038-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.169T>C​(p.Trp57Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000346 in 1,446,526 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W57G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 6.21

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 18 ACMG points.

• PM1: In a helix (size 17) in uniprot entity CFTR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117509038-T-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 7-117509038-T-C is Pathogenic according to our data. Variant chr7-117509038-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.169T>C	p.Trp57Arg	missense_variant	3/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.169T>C	p.Trp57Arg	missense_variant	3/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1446526 Hom.: 0 Cov.: 28 AF XY: 0.00000416 AC XY: 3 AN XY: 720792

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: 0.0000944

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000540 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:4 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2021	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Trp57 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7544319, 29805046). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 28830496, 16051530, Invitae). ClinVar contains an entry for this variant (Variation ID: 53346). This variant is present in population databases (rs397508272). This sequence change replaces tryptophan with arginine at codon 57 of the CFTR protein (p.Trp57Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 10, 2023	The p.W57R variant (also known as c.169T>C), located in coding exon 3 of the CFTR gene, results from a T to C substitution at nucleotide position 169. The tryptophan at codon 57 is replaced by arginine, an amino acid with dissimilar properties. This variant has been detected in conjunction with a pathogenic mutation in CFTR by our laboratory; however, the phase (whether in cis or trans) is not known. This alteration has also been identified in multiple individuals diagnosed with cystic fibrosis (Kinnunen S et al. J. Cyst. Fibros., 2005 Dec;4:233-7; De Wachter E et al. Orphanet J Rare Dis, 2017 Aug;12:142; Auzenbaha M et al. Diagnostics (Basel), 2022 Nov;12:). Based on internal structural analysis, this alteration is more disruptive than known pathogenic variants nearby (Liu F et al. Cell, 2017 Mar;169:85-95.e8). Furthermore, an in vitro study showed that this tryptophan residue is essential for processing of the CFTR protein (Cormet-Boyaka E et al. Proc. Natl. Acad. Sci. U.S.A., 2004 May;101:8221-6). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 15, 2023	Variant summary: CFTR c.169T>C (p.Trp57Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250754 control chromosomes. c.169T>C has been reported in the literature in individuals affected with Cystic Fibrosis (Duursma_2022, VanBiervliet_2018, Raraigh_2022, Sickkids_database). In addition another missense variant altering this amino acid (p.Trp57Gly) has been classified as pathogenic in ClinVar, supporting the functional importance of this residue of the protein. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics and Genomics, Karolinska University Hospital

Oct 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;.;T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.;.;.;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-9.3	D;.;.;D;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D;.;.;D;.
Sift4G	Uncertain	0.0020	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.97
MutPred		0.88		Gain of disorder (P = 0.0354);Gain of disorder (P = 0.0354);Gain of disorder (P = 0.0354);Gain of disorder (P = 0.0354);Gain of disorder (P = 0.0354);
MVP		1.0
MPC		0.012
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.93
gMVP		0.98

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: rs397508272; hg19: chr7-117149092;