chr7-117504279-G-T

Variant names:

• chr7-117504279-G-T
• rs397508797
• NM_000492.4:c.80G>T

Variant summary

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

The NM_000492.4(CFTR):​c.80G>T​(p.Gly27Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. G27R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71

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 topological_domain Cytoplasmic (size 76) in uniprot entity CFTR_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) 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 chr7-117504278-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.80G>T	p.Gly27Val	missense_variant	Exon 2 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.80G>T	p.Gly27Val	missense_variant	Exon 2 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 19, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CFTR c.80G>T (p.Gly27Val) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The variant of interest has not been found in 120864 control chromosomes (ExAC). A publication, Zietkiewicz_2013 cites the variant in a compound heterozygote CF individual, G27V/deltaF508. Two poster abstracts, Norek_2012 and Panickar_2016, cites the variant in 3 pts (2 homozygotes and 1 single variant identified pt), but these poster abstracts need to be cautiously considered due to limited available information. However, it should be noted another variant at this location, c.80G>A (p.G27E) has been reported in a compound heterozygote individual with a mild phenotype (database: sickkids). Therefore, taking all available lines of evidence, the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Pathogenic," until additional information becomes available (ie, clinical and functional studies). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;.;.;H
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-7.6	D;.;.;D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.99
MutPred		0.69		Gain of methylation at K26 (P = 0.0379);Gain of methylation at K26 (P = 0.0379);Gain of methylation at K26 (P = 0.0379);Gain of methylation at K26 (P = 0.0379);Gain of methylation at K26 (P = 0.0379);
MVP		1.0
MPC		0.015
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.96

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: rs397508797; hg19: chr7-117144333;