rs121909006

chr7-117590360-T-Achr7-117590360-T-Cchr7-117590360-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.1687T>A(p.Tyr563Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000624 in 1,603,020 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y563D) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 7.41

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 hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain 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 chr7-117590360-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 53342.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 7-117590360-T-A is Pathogenic according to our data. Variant chr7-117590360-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 7114.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117590360-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1687T>A	p.Tyr563Asn	missense_variant	13/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1687T>A	p.Tyr563Asn	missense_variant	13/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250432 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135462

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000620 AC: 9 AN: 1450938 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 721598

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: 0.00000724

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:7

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1990	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 26, 2023	This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 563 of the CFTR protein (p.Tyr563Asn). This variant is present in population databases (rs121909006, gnomAD 0.0009%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 1376017, 2236053, 10923036, 12815607, 15858154, 17825628; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7114). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 10764788). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 13, 2022	The p.Y563N pathogenic mutation (also known as c.1687T>A), located in coding exon 13 of the CFTR gene, results from a T to A substitution at nucleotide position 1687. The tyrosine at codon 563 is replaced by asparagine, an amino acid with dissimilar properties. This mutation was observed in a pancreatic sufficient individual with cystic fibrosis (CF) who was also heterozygous for a nonsense alteration; however, phase (cis or trans) was not determined (Kerem BS et al. Proc. Natl. Acad. Sci. U.S.A., 1990 Nov;87:8447-51). In another study, this mutation was observed in trans with a nonsense alteration in an individual with CF (Fichou Y et al. J. Cyst. Fibros., 2008 Mar;7:168-73). In vitro expression analysis revealed that the p.Y563N mutation results in decreased levels of mature CFTR protein (Van Oene M et al. J. Biol. Chem., 2000 Jun;275:19577-84). Based on the available evidence, the p.Y563N is classified as a pathogenic mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 04, 2022	Variant summary: CFTR c.1687T>A (p.Tyr563Asn) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250432 control chromosomes. c.1687T>A has been reported in the literature in multiple individuals affected with Cystic Fibrosis (example, McCague_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <1% of normal CFTR activity in vitro (example, Han_2018). Multiple clinical diagnostic laboratories and an expert panel (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, reviewed by expert panel	research	CFTR2	Dec 08, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 22, 2018	- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

Cystic fibrosis;na:CFTR-related disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Mar 09, 2018

the variant causes a phenotype but regarding our data, we can't formally attribute it to CF, CFTR-RD or both -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 23, 2021

PP3, PP5, PM2_strong, PS1, PS3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;.;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.9	M;.;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.2	D;.;D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Uncertain	0.0050	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		1.0
MutPred		0.95		Loss of phosphorylation at Y563 (P = 0.0471);.;.;.;
MVP		1.0
MPC		0.013
ClinPred		1.0	D
GERP RS		4.8
Varity_R		1.0
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121909006; hg19: chr7-117230414;