rs75053309

chr7-117540309-C-Achr7-117540309-C-Gchr7-117540309-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_000492.4(CFTR):c.1079C>A(p.Thr360Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T360I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 3.00

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117540309-C-A is Pathogenic according to our data. Variant chr7-117540309-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 440459.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}. Variant chr7-117540309-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1079C>A	p.Thr360Lys	missense_variant	8/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1079C>A	p.Thr360Lys	missense_variant	8/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000139 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2015

The p.[(Q359K;T360K)] variant (also known as c.[1075C>A;1079C>A]), located in coding exon 8 of the CFTR gene, is the result of two separate variants, p.Q359K (c.1075C>A) and p.T360K (c.1079C>A), being detected in cis. The glutamine at codon 359 and the threonine at codon 360 are both replaced by lysine, an amino acid with similar properties. The p.[(Q359K;T360K)] variant was detected in the homozygous state in patients affected with cystic fibrosis from three unrelated Georgian Jewish families (Shoshani T et al. Genomics. 1993;15(1):236-7). The p.Q359K and p.T360K variants were previously reported in the SNPDatabase as rs76879328 and rs75053309, respectively. These variants were not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, these variants were not observed in 6503 samples (13006 alleles) with coverage at this position. The glutamine at codon 359 is highly conserved in available vertebrate species, and the p.Q359K alteration is predicted to be probably damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. The threonine at codon 360 is not well conserved in available vertebrate species, and the p.T360K alteration is predicted to be benign and tolerated by PolyPhen and SIFT in silico analyses, respectively. Based on the majority of available evidence to date, the p.[(Q359K;T360K)] variant is likely to be pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 23, 2021

Variant summary: CFTR c.1079C>A (p.Thr360Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251008 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.1079C>A has not been reported in isolation in literature among individuals affected with Cystic Fibrosis. It has however been observed as part of a multinucleotide variation, that is variably annotated either as Q359K/T360K, p.[Gln359Lys;Thr360Lys], c.[1075C>A;1079C>A], or c.1075_1079delCAAACinsAAAAA or p.Gln359_Thr360delinsLysLys (example, Shoshani_1993, Wilschanski_1999, Bobadilla_2002, Sugarman_2004, Heim_2004, Chevalier-Porst_1994, Heim_2001, Petreska_1998, Schrijver_2005, Sosnay_2013, Castellani_2008, Petrova_2020). These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Cystic Fibrosis. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect in isolation (Sosnay_2013). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant in isolation was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.41	T;.;.;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.090
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.59	D;D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.23	N;.;.;.;N
MutationTaster	Benign	0.98	D;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.4	N;.;.;N;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.018	D;.;.;D;.
Sift4G	Uncertain	0.012	D;.;.;D;.
Polyphen		0.33	B;.;.;.;.
Vest4		0.83
MutPred		0.69		Gain of ubiquitination at T360 (P = 0.0289);Gain of ubiquitination at T360 (P = 0.0289);Gain of ubiquitination at T360 (P = 0.0289);.;Gain of ubiquitination at T360 (P = 0.0289);
MVP		0.98
MPC		0.0037
ClinPred		0.70	D
GERP RS		2.4
Varity_R		0.37
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs75053309; hg19: chr7-117180363;