chr7-117591978-C-T

Variant names:

• chr7-117591978-C-T
• rs397508308
• NM_000492.4:c.1811C>T

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.1811C>T​(p.Thr604Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,246 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. T604S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 7.28
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 18 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 chr7-117591977-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 4278170.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 7-117591978-C-T is Pathogenic according to our data. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117591978-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 53395.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1811C>T	p.Thr604Ile	missense_variant	Exon 14 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1811C>T	p.Thr604Ile	missense_variant	Exon 14 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446246 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718792

African (AFR) AF: 0.00 AC: 0 AN: 32292

American (AMR) AF: 0.00 AC: 0 AN: 40718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25396

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107816

Other (OTH) AF: 0.00 AC: 0 AN: 59626

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:3 Uncertain:1

Dec 18, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 16, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr604 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 15858154, 26277102; Invitae), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 53395). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 26277102). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 604 of the CFTR protein (p.Thr604Ile). -

Cystic fibrosis;C5924204:CFTR-related disorder Pathogenic:1

Mar 09, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;.;D;.
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.6	H;.;.;.
PhyloP100		7.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.8	D;.;D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;.;D;.
Sift4G	Uncertain	0.011	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.99
MutPred		0.97		Loss of disorder (P = 0.0634);.;.;.;
MVP		1.0
MPC		0.016
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.84
gMVP		0.97
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397508308; hg19: chr7-117232032;