rs1265244783

Positions:

• chr7-117530984-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The ENST00000003084.11(CFTR):​c.359C>T​(p.Ala120Val) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,326 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. A120T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CFTR ENST00000003084.11 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 6.18

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 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in ENST00000003084.11
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117530983-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53774.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=12, not_provided=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.359C>T	p.Ala120Val	missense_variant	4/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.359C>T	p.Ala120Val	missense_variant	4/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461326 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 726956

Gnomad4 AFR exome AF: 0.00

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: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 08, 2021	This sequence change replaces alanine with valine at codon 120 of the CFTR protein (p.Ala120Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. 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	Ambry Genetics	Oct 24, 2022	The p.A120V variant (also known as c.359C>T), located in coding exon 4 of the CFTR gene, results from a C to T substitution at nucleotide position 359. The alanine at codon 120 is replaced by valine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

CFTR-related disorder Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 16, 2024	The CFTR c.359C>T variant is predicted to result in the amino acid substitution p.Ala120Val. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 31, 2018	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 08, 2024

Variant summary: CFTR c.359C>T (p.Ala120Val) results in a non-conservative amino acid change located in the first transmembrane domain (IPR011527) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250898 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.359C>T in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 526016). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;.;.;T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.6	M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	N;.;.;N;.
REVEL	Pathogenic	0.74
Sift	Uncertain	0.011	D;.;.;D;.
Sift4G	Uncertain	0.0030	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.83
MutPred		0.72		Loss of disorder (P = 0.0972);Loss of disorder (P = 0.0972);Loss of disorder (P = 0.0972);Loss of disorder (P = 0.0972);Loss of disorder (P = 0.0972);
MVP		1.0
MPC		0.0087
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.77
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1265244783; hg19: chr7-117171038;