NM_000492.4:c.571T>G

Variant names:

• chr7-117534357-T-G
• rs141482808
• NM_000492.4:c.571T>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PP2 PP3_Moderate PP5_Very_Strong

The NM_000492.4(CFTR):​c.571T>G​(p.Phe191Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000182 in 1,536,306 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 Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV003915092: Published functional studies suggest a damaging effect: decreased protein expression and reduced channel activity (McCravy 2020); SCV004226571: PS3; SCV000697035: Experimental evidence evaluating an impact on protein function suggests the variant disrupts expression of the mature protein and ion transport, which can be corrected by drug treatment and results in approximately 4.58% of normal chloride channel conductance relative to wild type (McCravy_2020, Bihler_2024).; SCV005346812: "In vitro, and in vivo functional and biochemical studies using human nasal epithelial cells demonstrated diminished protein expression and reduced ion transport which improved with combination therapy treatment (McCravy et al. 2020. PubMed ID: 32265312)."".

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:16 U:1
• Conservation: PhyloP100: 5.37
• Publications: 8 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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV003915092: Published functional studies suggest a damaging effect: decreased protein expression and reduced channel activity (McCravy 2020); SCV004226571: PS3; SCV000697035: Experimental evidence evaluating an impact on protein function suggests the variant disrupts expression of the mature protein and ion transport, which can be corrected by drug treatment and results in approximately 4.58% of normal chloride channel conductance relative to wild type (McCravy_2020, Bihler_2024).; SCV005346812: "In vitro, and in vivo functional and biochemical studies using human nasal epithelial cells demonstrated diminished protein expression and reduced ion transport which improved with combination therapy treatment (McCravy et al. 2020. PubMed ID: 32265312)."
• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 29 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 7-117534357-T-G is Pathogenic according to our data. Variant chr7-117534357-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 495953.Status of the report is reviewed_by_expert_panel, 3 stars.

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.571T>G	p.Phe191Val	missense	Exon 5 of 27	NP_000483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.571T>G	p.Phe191Val	missense	Exon 5 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.571T>G	p.Phe191Val	missense	Exon 5 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.571T>G	p.Phe191Val	missense	Exon 5 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250352 AF XY: 0.00000738

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 18 AN: 1384122 Hom.: 0 Cov.: 23 AF XY: 0.00000721 AC XY: 5 AN XY: 693418

African (AFR) AF: 0.000439 AC: 14 AN: 31910

American (AMR) AF: 0.0000224 AC: 1 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25628

East Asian (EAS) AF: 0.00 AC: 0 AN: 39298

South Asian (SAS) AF: 0.00 AC: 0 AN: 84636

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1041720

Other (OTH) AF: 0.0000518 AC: 3 AN: 57922

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74350

African (AFR) AF: 0.000193 AC: 8 AN: 41454

American (AMR) AF: 0.000131 AC: 2 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000636 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	1	-	Cystic fibrosis (7)
3	-	-	not provided (3)
2	-	-	CFTR-related disorder (2)
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	-	-	Cystic fibrosis;C5924204:CFTR-related disorder (1)
1	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.89
Sift	Benign	0.081	T
Sift4G	Uncertain	0.0050	D
Polyphen		0.95	P
Vest4		0.89
MVP		0.99
MPC		0.015
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.83
Mutation Taster		=7/93	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
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: rs141482808; hg19: chr7-117174411;