rs1554392023

Positions:

• chr7-117610592-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000492.4(CFTR):​c.3062C>T​(p.Pro1021Leu) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1021S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.52

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 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 chr7-117610591-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53643.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1, not_provided=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.932
• PP5: Variant 7-117610592-C-T is Pathogenic according to our data. Variant chr7-117610592-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 455774.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3062C>T	p.Pro1021Leu	missense_variant	19/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3062C>T	p.Pro1021Leu	missense_variant	19/27	1	NM_000492.4	P2
	ENST00000456270.1	n.178-5603G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 18, 2023	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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro1021 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8663008; http//www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=1263). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 455774). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 29520692). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1021 of the CFTR protein (p.Pro1021Leu). -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 20, 2015	The p.P1021L variant (also known as c.3062C>T), located in coding exon 19 of the CFTR gene, results from a C to T substitution at nucleotide position 3062. The proline at codon 1021 is replaced by leucine, an amino acid with some similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;.;D;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.8	M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-7.0	D;.;.;D;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.94
MutPred		0.73		Loss of glycosylation at T1019 (P = 0.1148);.;.;.;.;
MVP		0.99
MPC		0.0055
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.91
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: rs1554392023; hg19: chr7-117250646;