Genetic Variant NM_000492.4:c.1397C>A (chr7-117559468-C-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000492.4(CFTR):c.1397C>A(p.Ser466*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S466S) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CFTR
NM_000492.4 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:3

Conservation

PhyloP100: 7.44

Publications

63 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-117559468-C-A is Pathogenic according to our data. Variant chr7-117559468-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 53244.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.1397C>A	p.Ser466*	stop_gained	Exon 11 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1 link	n.221+1265G>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.1397C>A	p.Ser466*	stop_gained	Exon 11 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1446926

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720972

African (AFR)

AF:

0.00

AC:

AN:

32830

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26056

East Asian (EAS)

AF:

0.00

AC:

AN:

39538

South Asian (SAS)

AF:

0.00

AC:

AN:

85932

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099020

Other (OTH)

AF:

0.00

AC:

AN:

59862

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:1

Mar 17, 2017

CFTR2

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:research

- -

CFTR-related disorder

Pathogenic:1

Mar 17, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cystic fibrosis;C5924204:CFTR-related disorder

Pathogenic:1

Jan 29, 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

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

PhyloP100

7.4

Vest4

0.98

GERP RS

5.5

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over