rs397508542

Variant names:

• chr7-117611763-G-A
• NM_000492.4:c.3322G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-117611763-G-A
• chr7-117611763-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000492.4(CFTR):​c.3322G>A​(p.Val1108Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,292 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 (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.71

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]

ENSG00000083622 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a helix (size 50) in uniprot entity CFTR_HUMAN there are 11 pathogenic changes around while only 0 benign (100%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.874

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3322G>A	p.Val1108Ile	missense_variant	Exon 20 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3322G>A	p.Val1108Ile	missense_variant	Exon 20 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461292 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cystic fibrosis Uncertain:1

Dec 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V1108I variant (also known as c.3322G>A), located in coding exon 20 of the CFTR gene, results from a G to A substitution at nucleotide position 3322. The valine at codon 1108 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is conserved. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;.;.;T;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	1.6	L;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.31	N;.;.;N;.
REVEL	Pathogenic	0.66
Sift	Benign	0.056	T;.;.;D;.
Sift4G	Uncertain	0.0030	D;.;.;D;.
Polyphen		0.95	P;.;.;.;.
Vest4		0.63
MutPred		0.74		Loss of catalytic residue at V1108 (P = 0.1439);.;.;.;.;
MVP		1.0
MPC		0.0052
ClinPred		0.73	D
GERP RS		5.4
Varity_R		0.47
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-117251817;