7-117559500-C-G

Variant names:

• chr7-117559500-C-G
• rs139054556
• NM_000492.4:c.1429C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1 PP2

The NM_000492.4(CFTR):​c.1429C>G​(p.Pro477Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,458,850 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P477L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.68
• Publications: 6 publications found

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]

CFTR-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 uncertain in NM_000492.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1429C>G	p.Pro477Ala	missense	Exon 11 of 27	NP_000483.3
	CFTR-AS1	NR_149084.1		n.221+1233G>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1429C>G	p.Pro477Ala	missense	Exon 11 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.1429C>G	p.Pro477Ala	missense	Exon 11 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.1339C>G	p.Pro447Ala	missense	Exon 10 of 26	ENSP00000389119.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458850 Hom.: 0 Cov.: 29 AF XY: 0.00000275 AC XY: 2 AN XY: 726014

African (AFR) AF: 0.0000300 AC: 1 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86200

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109458

Other (OTH) AF: 0.0000166 AC: 1 AN: 60300

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	D
Eigen	Benign	0.045
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.4	L
PhyloP100		4.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.56
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Polyphen		0.079	B
Vest4		0.39
MutPred		0.65		Loss of ubiquitination at K481 (P = 0.0613)
MVP		0.99
MPC		0.0041
ClinPred		0.59	D
GERP RS		4.6
Varity_R		0.33
gMVP		0.93
Mutation Taster		=24/76	disease causing

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

Other links and lift over

dbSNP: rs139054556; hg19: chr7-117199554;