rs150212784

Variant names:

• chr7-117611595-T-G
• rs150212784
• NM_000492.4:c.3154T>G

Your query was ambiguous. Multiple possible variants found:

• chr7-117611595-T-G
• chr7-117611595-T-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS3 PM1 PP2

The NM_000492.4(CFTR):​c.3154T>G​(p.Phe1052Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000464 in 1,608,938 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as drug response (★★★). ClinVar reports functional evidence for this variant: "SCV000052171: "In vitro experiments indicated that the variant mildly affects chloride channel function (Sosnay_2013, Van Goor_2014, Bihler_2024). In addition, this variant was found to alter the regulation and gating properties of chloride channels, though cAMP-stimulated efflux of chlorine channel was normal (Seibert_1996, Cotton_1996)."" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1052S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: drug response reviewed by expert panel P:22 U:9 O:1
• Conservation: PhyloP100: 7.97
• Publications: 89 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)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000052171: "In vitro experiments indicated that the variant mildly affects chloride channel function (Sosnay_2013, Van Goor_2014, Bihler_2024). In addition, this variant was found to alter the regulation and gating properties of chloride channels, though cAMP-stimulated efflux of chlorine channel was normal (Seibert_1996, Cotton_1996)."; SCV001180126: "In vitro studies demonstrated that this variant does not impact maturation of CFTR protein, but reduces CFTR function (Cotten JF et al. J. Biol. Chem., 1996 Aug;271:21279-84; Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45; Sosnay PR et al. Nat Genet, 2013 Oct;45:1160-7; Van Goor F et al. J Cyst Fibros, 2014 Jan;13:29-36)."; SCV000601088: In addition, functional studies indicated that this variant did not hinder CFTR protein processing and chloride channel conductance, but it did reduce certain gating and kinetic properties of the chloride channel (PMIDs: 8702904 (1996), 8662892 (1996), 23891399 (2014)).; SCV001501421: PS3:Supporting; SCV000883565: Functional studies indicate that the variant protein has normal maturation and conductance (Sosnay 2013, Van Goor 2014), but altered channel kinetics (Cotten 1996, Seibert 1996).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.3154T>G	p.Phe1052Val	missense	Exon 20 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.177+4634A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3154T>G	p.Phe1052Val	missense	Exon 20 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.3154T>G	p.Phe1052Val	missense	Exon 20 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.3067T>G	p.Phe1023Val	missense	Exon 19 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.000381 AC: 58 AN: 152114 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000647 AC: 162 AN: 250362 AF XY: 0.000695

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000611

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.000919

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000472 AC: 688 AN: 1456824 Hom.: 1 Cov.: 30 AF XY: 0.000488 AC XY: 354 AN XY: 725064

African (AFR) AF: 0.000150 AC: 5 AN: 33372

American (AMR) AF: 0.000762 AC: 34 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00215 AC: 56 AN: 26090

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

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86112

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53328

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5758

European-Non Finnish (NFE) AF: 0.000471 AC: 522 AN: 1107704

Other (OTH) AF: 0.000598 AC: 36 AN: 60204

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152114 Hom.: 0 Cov.: 31 AF XY: 0.000363 AC XY: 27 AN XY: 74302

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00118 AC: 18 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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: 0.000456 AC: 31 AN: 68014

Other (OTH) AF: 0.00143 AC: 3 AN: 2092

Alfa AF: 0.000786 Hom.: 0

Bravo AF: 0.000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000610 AC: 74

EpiCase AF: 0.00147

EpiControl AF: 0.00143

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
8	3	-	Cystic fibrosis (11)
5	4	-	not provided (9)
3	1	-	Hereditary pancreatitis (4)
2	1	-	CFTR-related disorder (3)
2	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (2)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
-	-	-	ivacaftor response - Efficacy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MVP		1.0
MPC		0.014
ClinPred		0.11	T
GERP RS		5.7
PromoterAI		0.0086	Neutral
Varity_R		0.96
gMVP		0.97
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs150212784; hg19: chr7-117251649;