rs76727851

chr7-117540324-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000492.4(CFTR):c.1094T>C(p.Leu365Pro) variant causes a missense 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L365L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 7.54

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1094T>C	p.Leu365Pro	missense_variant	8/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1094T>C	p.Leu365Pro	missense_variant	8/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.000140 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 26, 2018	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 07, 2017	The p.L365P variant (also known as c.1094T>C), located in coding exon 8 of the CFTR gene, results from a T to C substitution at nucleotide position 1094. The leucine at codon 365 is replaced by proline, an amino acid with similar properties. This variant was identified in a Spanish cystic fibrosis cohort; however, specific genotype and phenotype information were not provided (Alonso MJ et al. Ann. Hum. Genet., 2007 Mar;71:194-201). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.3	M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N;.;.;N;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.015	D;.;.;D;.
Sift4G	Pathogenic	0.0010	D;.;.;D;.
Polyphen		0.90	P;.;.;.;.
Vest4		0.91
MutPred		0.92		Loss of stability (P = 0.0111);Loss of stability (P = 0.0111);Loss of stability (P = 0.0111);.;Loss of stability (P = 0.0111);
MVP		0.99
MPC		0.0046
ClinPred		0.90	D
GERP RS		4.1
Varity_R		0.85
gMVP		0.97

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: rs76727851; hg19: chr7-117180378; COSMIC: COSV50063373;