Genetic Variant CFTR:p.Thr465Ile (chr7-117559465-C-T) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000492.4(CFTR):c.1394C>T(p.Thr465Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000692 in 1,444,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense, splice_region

Scores

Splicing: ADA: 0.9786

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.86

Variant links:

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 links:

CFTR-AS1 (HGNC:40144): (CFTR antisense RNA 1)

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.1394C>T	p.Thr465Ile	missense_variant, splice_region_variant	Exon 11 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730
CFTR-AS1	NR_149084.1 link	n.221+1268G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.1394C>T	p.Thr465Ile	missense_variant, splice_region_variant	Exon 11 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1444170

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719794

show subpopulations

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:

9.12e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:1

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM5, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;.;.;D;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;T;T;D;T

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.8

H;.;.;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.2

D;.;.;D;.

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

D;.;.;D;.

Sift4G

Pathogenic

0.0010

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.86

MutPred

0.93

Gain of stability (P = 0.028);.;.;.;.;

MVP

1.0

MPC

0.012

ClinPred

1.0

GERP RS

5.5

Varity_R

0.97

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.82

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over