rs371107552

Positions:

• chr7-117548701-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000492.4(CFTR):​c.1270G>A​(p.Gly424Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,613,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G424G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:12
• Conservation: PhyloP100: 3.36

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]

CFTR-AS1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 172 pathogenic changes around while only 15 benign (92%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13353205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1270G>A	p.Gly424Ser	missense_variant	10/27	ENST00000003084.11
CFTR-AS1	NR_149084.1	n.222-6162C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1270G>A	p.Gly424Ser	missense_variant	10/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152062 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000934 AC: 23 AN: 246210 Hom.: 0 AF XY: 0.0000749 AC XY: 10 AN XY: 133598

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.0000292

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: 0.000163

Gnomad OTH exome AF: 0.000335

GnomAD4 exome AF: 0.000207 AC: 303 AN: 1461124 Hom.: 0 Cov.: 36 AF XY: 0.000187 AC XY: 136 AN XY: 726868

Gnomad4 AFR exome AF: 0.0000598

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: 0.000264

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152062 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74272

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 16, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 19, 2019	This CFTR variant (rs371107552) is rare (<0.1%) in large population datasets1,2 (gnomAD: 24/277606 total alleles; 0.0087%, no homozygotes). Six submitters in ClinVar classify the clinical significance of this variant as uncertain. One study has demonstrated that CFTR c.1270G>A may decrease inclusion of exon 10 (legacy exon 9) during splicing; however, bioinformatics tools do not predict this variant will alter typical splicing patterns. Two bioinformatics tools predict this amino acid substitution will be tolerated. The glycine residue at this position is not well conserved across species assessed. Due to insufficient evidence, we consider the clinical significance of c.1270G>A uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 04, 2022	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 424 of the CFTR protein (p.Gly424Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with rheumatoid arthritis and bronchiectasis (PMID: 21131649). ClinVar contains an entry for this variant (Variation ID: 286406). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 12732620). 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	Ambry Genetics	Jan 17, 2024	The p.G424S variant (also known as c.1270G>A), located in coding exon 10 of the CFTR gene, results from a G to A substitution at nucleotide position 1270. The glycine at codon 424 is replaced by serine, an amino acid with similar properties. This alteration was reported in two related individuals with diffuse bronchiectasis and rheumatoid arthritis; one of the individuals also carried the p.G576A alteration but the phase was unclear (Pu&eacute;chal X. et al., Ann. Rheum. Dis. 2011 Apr; 70(4):653-9). One study of Hep3B cells transfected with this alteration showed some mRNA transcripts with skipping of exon 9 in addition to wild type mRNA transcripts (Pagani F et al., J. Biol. Chem. 2003 Jul; 278(29):26580-8). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 02, 2022	Identified in the single heterozygous state or with a second CFTR variant, phase unknown, in an asymptomatic individual and individuals with bronchiectasis (Puchal et al., 2011; Claustres et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25735457, 12732620, 11504857, 23420618, 21131649, 29669919, 15536480, 16251901, 28603918) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 03, 2017	The CFTR c.1270G>A; p.Gly424Ser variant (rs371107552) has been reported in two individuals from a family with rheumatoid arthritis and bronchiectasis (Puechal 2011), and reported to cause exon 9 skipping in a portion of transcripts (Pagani 2003, Aissat 2013). However, this variant occurs in a weakly conserved amino acid (Chen 2001), and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be tolerated. This variant is reported in the ClinVar database as uncertain (Variation ID: 286406), and observed in general population databases with overall allele frequencies of 0.015 percent (2/12966 alleles, Exome Variant Server), and 0.008 percent (21/272812 alleles, Genome Aggregation Database), but is considered a low confidence variant in the database due to segmental duplication. Based on the above information, the clinical significance of p.Gly424Ser is uncertain at this time. REFERENCES Link to ClinVar database for p.Gly424Ser: https://www.ncbi.nlm.nih.gov/clinvar/variation/286406/ Aissat A et al. Combined computational-experimental analyses of CFTR exon strength uncover predictability of exon-skipping level. Hum Mutat. 2013 Jun;34(6):873-81. Chen JM et al. A combined analysis of the cystic fibrosis transmembrane conductance regulator: implications for structure and disease models. Mol Biol Evol. 2001 Sep;18(9):1771-88. Pagani F et al. Missense, nonsense, and neutral mutations define juxtaposed regulatory elements of splicing in cystic fibrosis transmembrane regulator exon 9. J Biol Chem. 2003 Jul 18;278(29):26580-8. Puechal X et al. Mutations of the cystic fibrosis gene in patients with bronchiectasis associated with rheumatoid arthritis. Ann Rheum Dis. 2011 Apr;70(4):653-9. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 20, 2016	The p.Gly424Ser variant in CFTR has been reported in at least 1 Caucasian indivi dual with diffuse bronchiectasis and rheumatoid arthritis. Multiple members of t his family are reported to be affected, but this variant does not segregate with disease (Puechal 2011). This variant has been identified in 9/57094 European ch romosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EV S/; dbSNP rs371107552). Computational prediction tools and conservation analysis suggest that the p.Gly424Ser variant may not impact the protein, though this in formation is not predictive enough to rule out pathogenicity. In summary, the cl inical significance of the p.Gly424Ser variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 14, 2023	Variant summary: CFTR c.1270G>A (p.Gly424Ser) results in a non-conservative amino acid change located in the ABC transporter-like domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, the variant resulted in reduced inclusion of exon 9 in a mini-gene assay (Pagani_2003). The variant allele was found at a frequency of 9.7e-05 in 247386 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (9.7e-05 vs 0.013), allowing no conclusion about variant significance. c.1270G>A has been reported in two affected patients with rheumatoid arthritis and diffuse bronchiectasis (RA-DB) from one family (Puechal_2011) without strong evidence for pathogenicity. The Sickkids database also reports a female patient with bronchiectasis harboring this variant. The variant has also been reported in two patients with pancreatic cancer (Tamura_2018), and in a large Cystic Fibrosis patient cohort (Raraigh_2022). These reports do not provide unequivocal conclusions about association of the variant with Non-Classic Cystic Fibrosis. The following publications have been ascertained in the context of this evaluation (PMID: 23420618, 11504857, 28603918, 15536480, 12732620, 16251901, 21131649, 25735457, 29669919, 34782259). Eleven ClinVar submitters have assessed the variant since 2014: all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.65	T;T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	-0.090	N;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.46
Sift	Benign	0.075	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.0	B;.
Vest4		0.72
MVP		0.99
MPC		0.0040
ClinPred		0.044	T
GERP RS		4.8
Varity_R		0.071
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs371107552; hg19: chr7-117188755;