rs397508488

chr7-117610577-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000492.4(CFTR):c.3047T>C(p.Phe1016Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,288 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3 O:1
• Conservation: PhyloP100: 7.62

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, 10 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 7-117610577-T-C is Pathogenic according to our data. Variant chr7-117610577-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53640.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=3, not_provided=1}. Variant chr7-117610577-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.3047T>C	p.Phe1016Ser	missense_variant	19/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.3047T>C	p.Phe1016Ser	missense_variant	19/27	1	NM_000492.4	P2
	ENST00000456270.1	n.178-5588A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251134 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461288 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726946

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Uncertain:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 27, 2022	CFTR variant associated with varying clinical consequence. See www.CFTR2.org for phenotype information. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 31, 2023	The p.F1016S variant (also known as c.3047T>C), located in coding exon 19 of the CFTR gene, results from a T to C substitution at nucleotide position 3047. The phenylalanine at codon 1016 is replaced by serine, an amino acid with highly dissimilar properties. This variant has been detected in conjunction with p.L102R in the CFTR gene in multiple individuals; family studies indicated that these two variants are on the same chromosome (Ambry internal data). This variant was first reported in an individual with cystic fibrosis in conjunction with a frameshift variant (Alper OM et al. Hum. Mutat., 2004 Oct;24:353). This variant has also been detected in an individual with an abnormal newborn screening with elevated sweat chloride levels and pancreatic insufficiency in conjunction with p.L102R and p.F508del (Salinas DB et al. PLoS One, 2016 May;11:e0155624). In CFBE cells, this variant had significantly reduced CFTR function compared to wild type, and the function improved with CFTR modulators (Han ST et al. JCI Insight, 2018 07;3:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 20, 2021	This variant has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 15365999, 27214204; Invitae). This variant is present in population databases (rs397508488, ExAC 0.009%). This sequence change replaces phenylalanine with serine at codon 1016 of the CFTR protein (p.Phe1016Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. ClinVar contains an entry for this variant (Variation ID: 53640). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). Experimental studies have shown that this variant affects CFTR function (PMID: 30046002). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 25, 2024

Variant summary: CFTR c.3047T>C (p.Phe1016Ser) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251134 control chromosomes. c.3047T>C has been reported in the literature in at least one individual affected with Cystic Fibrosis (e.g. Alper_2004, Kharazzi_2015).The variant has also been detected in one patient reportedly affected by CF who was genotyped by our laboratory. The variant was found to be in cis with another variant of uncertain significance, c.305T>C (p.Leu102Arg), in at least two individuals (internal testing). At least one functional study reports this variant to result in decreased CFTR activity (Han_2018). The following publications have been ascertained in the context of this evaluation (PMID: 15365999, 30046002, 26574590, 25735457, 27214204, 18556774, 15300780). ClinVar contains an entry for this variant (Variation ID: 53640). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.;.;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Pathogenic	0.57	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.1	M;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N;.;.;N;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		0.92	P;.;.;.;.
Vest4		0.95
MutPred		0.82		Loss of catalytic residue at F1016 (P = 0.0557);.;.;.;.;
MVP		1.0
MPC		0.0035
ClinPred		0.67	D
GERP RS		6.2
Varity_R		0.79
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: rs397508488; hg19: chr7-117250631;