rs397508467

chr7-117530921-C-T

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.296C>T(p.Pro99Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,790 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. P99A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3 O:1
• Conservation: PhyloP100: 7.50

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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 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 chr7-117530921-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1704257.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 7-117530921-C-T is Pathogenic according to our data. Variant chr7-117530921-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 53610.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117530921-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.296C>T	p.Pro99Leu	missense_variant	4/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.296C>T	p.Pro99Leu	missense_variant	4/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251082 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135688

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460790 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726790

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: 0.00000900

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2020	This variant has been observed in individual(s) with cystic fibrosis (PMID: 11732487, 14872121). ClinVar contains an entry for this variant (Variation ID: 53610). 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 has been reported to affect CFTR protein function (PMID: 29805046, 866 3008). This variant is present in population databases (rs397508467, ExAC 0.003%). This sequence change replaces proline with leucine at codon 99 of the CFTR protein (p.Pro99Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. -
Pathogenic, reviewed by expert panel	research	CFTR2	Dec 08, 2017	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -

Cystic fibrosis;na:CFTR-related disorder 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-10	D;D;.;.;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;.;.;D;.
Polyphen		1.0	.;D;.;.;.;.
Vest4		0.96
MutPred		0.91		.;Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);Gain of stability (P = 0.0258);
MVP		1.0
MPC		0.017
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.96
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: rs397508467; hg19: chr7-117170975;