rs147422190

Variant names:

• chr7-117548758-G-T
• rs147422190
• NM_000492.4:c.1327G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 PM1 PP2 PP5

The NM_000492.4(CFTR):​c.1327G>T​(p.Asp443Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000573 in 1,612,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000074287: Experimental studies have shown that this missense change affects CFTR protein function (PMID:22678879)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D443V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00060 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:20 U:5
• Conservation: PhyloP100: 2.77
• Publications: 23 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: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000074287: Experimental studies have shown that this missense change affects CFTR protein function (PMID: 22678879).; SCV000916180: Functional studies indicate that p.[Asp443Tyr;Gly576Ala;Arg668Cys] alters CFTR maturation and chloride conductance but retains some residual function, which is consistent with mild or moderate phenotypes.; SCV000919136: Several publications report experimental evidence evaluating an impact on protein function in isolation as well as part of the complex haplotype. The most pronounced isolated variant effect reports conflicting findings between studies ranging from no effect (El-Seedy_2012) to intermediate levels (Raraigh_2018) of chloride channel function (approximately 50% of WT levels) and a moderate alteration of CFTR maturation and localization (El-Seedy_2012).; SCV001171326: "In vitro functional studies showed that this alteration affects protein maturation. In one study, p.D443Y showed decreased chloride channel activity when co-expressed with p.G576A and p.R668C, but not when expressed alone in cultured cells (El-Seedy et al. Hum Mutat. 2012; 33(11);15557-65). In another study, this variant showed decreased chloride channel activity when expressed alone (Raraigh KS et al. Am. J. Hum. Genet. 2018 Jun;102(6):1062-1077)."; SCV002107092: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 22678879; 29805046) - PS3_supporting."; SCV001162789: At-least one publication reports experimental evidence evaluating an impact on protein function of these variants in isolation as well as part of the complex haplotype. In this study, the authors concluded that the combination of p.Gly576Ala and p.Arg668Cys affecting chloride channel activity coupled with p.Asp443Tyr effecting protein maturation would account for the pathogenicity of the overall haplotype (El-Seedy_2012). PMID 22678879
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 25 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.
• PP5: Variant 7-117548758-G-T is Pathogenic according to our data. Variant chr7-117548758-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53229.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1327G>T	p.Asp443Tyr	missense	Exon 10 of 27	NP_000483.3
	CFTR-AS1	NR_149084.1		n.222-6219C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1327G>T	p.Asp443Tyr	missense	Exon 10 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1327G>T	p.Asp443Tyr	missense	Exon 10 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1327G>T	p.Asp443Tyr	missense	Exon 10 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000264 AC: 64 AN: 242156 AF XY: 0.000297

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000499

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000600 AC: 876 AN: 1460654 Hom.: 0 Cov.: 36 AF XY: 0.000586 AC XY: 426 AN XY: 726584

African (AFR) AF: 0.0000299 AC: 1 AN: 33440

American (AMR) AF: 0.000381 AC: 17 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86160

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.000739 AC: 821 AN: 1111368

Other (OTH) AF: 0.000614 AC: 37 AN: 60282

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74484

African (AFR) AF: 0.000289 AC: 12 AN: 41582

American (AMR) AF: 0.000589 AC: 9 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000373 Hom.: 0

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000231 AC: 28

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
9	2	-	Cystic fibrosis (11)
5	1	-	not provided (6)
3	-	-	CFTR-related disorder (3)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
-	1	-	Hereditary pancreatitis (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.8
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.90	P
Vest4		0.79
MVP		0.99
MPC		0.0097
ClinPred		0.57	D
GERP RS		2.5
Varity_R		0.84
gMVP		0.93
Mutation Taster		=11/89	disease causing (ClinVar)

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: rs147422190; hg19: chr7-117188812;