rs762847468

chr7-117666942-C-Achr7-117666942-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000492.4(CFTR):c.4277C>A(p.Ser1426Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,760 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1426P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 7.20

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 6 ACMG points.

• PM1: In a domain ABC transporter 2 (size 233) in uniprot entity CFTR_HUMAN there are 67 pathogenic changes around while only 7 benign (91%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.4277C>A	p.Ser1426Tyr	missense_variant	27/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.4277C>A	p.Ser1426Tyr	missense_variant	27/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250796 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135556

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461760 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727176

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 06, 2023	The c.4277C>A (p.S1426Y) alteration is located in exon 27 (coding exon 27) of the CFTR gene. This alteration results from a C to A substitution at nucleotide position 4277, causing the serine (S) at amino acid position 1426 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 13, 2019	This CFTR variant has not been reported in the literature in patients with cystic fibrosis to our knowledge. It is classified as a variant of uncertain clinical significance in ClinVar by a single submitter. This variant is rare (<0.1%) in a large population dataset (gnomAD: 2/250796 total alleles; 0.0008%; no homozygotes). Three bioinformatic tools queried predict that this substitution would be probably be damaging and the serine residue at this position is evolutionarily conserved in all species assessed except for the Southern platyfish. We consider the clinical significance of c.4277C>A to be uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 16, 2022	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 1426 of the CFTR protein (p.Ser1426Tyr). This variant is present in population databases (rs762847468, gnomAD 0.003%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 32819855). ClinVar contains an entry for this variant (Variation ID: 618957). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 09, 2020

Variant summary: CFTR c.4277C>A (p.Ser1426Tyr) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) 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 250796 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4277C>A has been reported in the literature in individuals affected with advanced liver disease of indeterminate aetiology or Cystic fibrosis (Vilarinho_2014, da Silva Filho_2020). These reports do not provide unequivocal conclusions about association of the variant with Chronic Pancreatitis Risk. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

CFTR-related disorders Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jul 16, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2021

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with a clinical diagnosis of cystic fibrosis for which a second variant was not reported and in an individual with Alagille-like syndrome (Vilarinho 2014, da Silva Filho 2020); This variant is associated with the following publications: (PMID: 27535533, 25016221, 25880441, 32819855) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;T;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.4	D;D;.
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.76
MutPred		0.61		Loss of disorder (P = 0.0268);.;.;
MVP		0.99
MPC		0.0042
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.74
gMVP		0.78

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: rs762847468; hg19: chr7-117306996;