7-117504336-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_000492.4(CFTR):c.137C>T(p.Ala46Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000162 in 1,600,604 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A46D) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:11
• Conservation: PhyloP100: 6.12

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr7-117504336-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 53238.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2956459).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.137C>T	p.Ala46Val	missense_variant	2/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.137C>T	p.Ala46Val	missense_variant	2/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000319 AC: 8 AN: 250758 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135508

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000898 AC: 13 AN: 1448374 Hom.: 0 Cov.: 27 AF XY: 0.00000832 AC XY: 6 AN XY: 721476

Gnomad4 AFR exome AF: 0.000331

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74426

Gnomad4 AFR AF: 0.000313

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000470 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Dec 21, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 08, 2022	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 46 of the CFTR protein (p.Ala46Val). This variant is present in population databases (rs151020603, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 593277). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 02, 2020	The p.A46V variant (also known as c.137C>T), located in coding exon 2 of the CFTR gene, results from a C to T substitution at nucleotide position 137. The alanine at codon 46 is replaced by valine, an amino acid with similar properties. This amino acid position is highly 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 19, 2019	CFTR c.137C>T has not been reported in the literature, to our knowledge. This CFTR variant (rs151020603) is rare (<0.1%) in a large population dataset1 (gnomAD: 12/282150 total alleles; 0.004%; no homozygotes). There are conflicting interpretations of the pathogenicity of this variant in ClinVar. Three submitters classified it as a variant of uncertain clinical significance and one as likely pathogenic. Two bioinformatic tools queried predict that this substitution would be damaging, and the alanine residue at this position is highly evolutionarily conserved across all species assessed. This variant is located within the same residue as p.Ala46Asp, a previously reported alternate pathogenic missense variant. We consider the clinical significance of c.137C>T uncertain at this time. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 04, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 11, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 01, 2022	The CFTR c.137C>T; p.Ala46Val variant (rs151020603), to our knowledge, is not reported in the medical literature but is reported in the SickKids CFTR database in an individual with a positive newborn screen (see link). This variant is reported in ClinVar (Variation ID: 593277) and is found in the African population with an allele frequency of 0.05% (12/24960 alleles) in the Genome Aggregation Database. Additionally, another variant at this codon (c.137C>A, p.Ala46Asp) have been reported in individuals with cystic fibrosis and is considered pathogenic (Tzetis 1995, Van Goor 2014). The alanine at codon 46 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.468). However, given the lack of clinical and functional data, the significance of the p.Ala46Val variant is uncertain at this time. References: SickKids CFTR database: http://www.genet.sickkids.on.ca/cftr/Home.html Tzetis M et al. Identification of two novel mutations (296 + 1G-C and A46D) in exon 2 of the CFTR gene in Greek cystic fibrosis patients. Mol Cell Probes. 1995 Aug;9(4):283-5. PMID: 7477025. Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 Jan;13(1):29-36.PMID: 23891399. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 07, 2023

Variant summary: CFTR c.137C>T (p.Ala46Val) results in a non-conservative amino acid change in 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 3.2e-05 in 250758 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.137C>T has been reported in the literature as a non-informative genotype (second allele not specified) in at-least one individual reportedly affected with Cystic Fibrosis (example, daSilvaFilho_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32819855). A different variant located at the same codon (c.137C>A, p.Ala46Asp) has been classified as pathogenic, however, current evidence is insufficient to determine the effect of p.Ala46Val on protein function. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Congenital bilateral aplasia of vas deferens from CFTR mutation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;.;.;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.30	T;T;T;T;T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	1.7	L;.;.;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N;.;.;N;.
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.87
MVP		0.99
MPC		0.012
ClinPred		0.28	T
GERP RS		5.6
Varity_R		0.61
gMVP		0.89

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: rs151020603; hg19: chr7-117144390;