7-117611794-C-T

Variant names:

• chr7-117611794-C-T
• rs146521846
• NM_000492.4:c.3353C>T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_000492.4(CFTR):​c.3353C>T​(p.Ser1118Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,610,154 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: "SCV002600724: "At least two publications report experimental evidence evaluating an impact on protein function (example, Han_2018, Penmatsa_2009). The most pronounced variant effect results in <10% of normal CFTR residual function (Han_2018) and impaired maturation (Penmatsa_2009)."; SCV002606746: Several in vitro studies have suggested this mutation, which is located in transmembrane 11 domain, decreases the chloride channel voltage, gating, permeability and efficiency, and results in reduced function compared to wild type (Zhang et al. Biophys. J. 2000;79(1):298-313; Penmatsa et al Pediatr. Pulmonol. 2009;44(10):1003-9; Raraigh KS et al. Am J Hum Genet. 2018 06;102(6):1062-1077).; SCV002929527: Experimental studies have shown that this missense change affects CFTR function (PMID:10866956, 19774621, 29805046, 30046002).; SCV003923320: "In vitro studies have suggested this mutation, which is located in transmembrane 11 domain, decreases the chloride channel voltage, gating, permeability and efficiency, and results in reduced function compared to wild type (Planells-Cases R et al., 2000)."; SCV005348884: Functional studies show the p.Ser1118Phe substitution impacts normal protein function (Zhang et al. 2000. PubMed ID: 10866956; Penmatsa et al. 2009. PubMed ID: 19774621; Raraigh et al. 2018. PubMed ID: 29805046).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1118C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 O:1
• Conservation: PhyloP100: 7.56
• Publications: 7 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: Pathogenic. The variant received 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002600724: "At least two publications report experimental evidence evaluating an impact on protein function (example, Han_2018, Penmatsa_2009). The most pronounced variant effect results in <10% of normal CFTR residual function (Han_2018) and impaired maturation (Penmatsa_2009)."; SCV002606746: Several in vitro studies have suggested this mutation, which is located in transmembrane 11 domain, decreases the chloride channel voltage, gating, permeability and efficiency, and results in reduced function compared to wild type (Zhang et al. Biophys. J. 2000;79(1):298-313; Penmatsa et al Pediatr. Pulmonol. 2009;44(10):1003-9; Raraigh KS et al. Am J Hum Genet. 2018 06;102(6):1062-1077).; SCV002929527: Experimental studies have shown that this missense change affects CFTR function (PMID: 10866956, 19774621, 29805046, 30046002).; SCV003923320: "In vitro studies have suggested this mutation, which is located in transmembrane 11 domain, decreases the chloride channel voltage, gating, permeability and efficiency, and results in reduced function compared to wild type (Planells-Cases R et al., 2000)."; SCV005348884: Functional studies show the p.Ser1118Phe substitution impacts normal protein function (Zhang et al. 2000. PubMed ID: 10866956; Penmatsa et al. 2009. PubMed ID: 19774621; Raraigh et al. 2018. PubMed ID: 29805046).
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117611794-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53721.
• 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, 0.875
• PP5: Variant 7-117611794-C-T is Pathogenic according to our data. Variant chr7-117611794-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 53722.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.3353C>T	p.Ser1118Phe	missense	Exon 20 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.177+4435G>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.3353C>T	p.Ser1118Phe	missense	Exon 20 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.3353C>T	p.Ser1118Phe	missense	Exon 20 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.3266C>T	p.Ser1089Phe	missense	Exon 19 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151748 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 250416 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1458406 Hom.: 0 Cov.: 30 AF XY: 0.0000262 AC XY: 19 AN XY: 725724

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.00 AC: 0 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53210

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1109226

Other (OTH) AF: 0.0000166 AC: 1 AN: 60286

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151748 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74080

African (AFR) AF: 0.0000484 AC: 2 AN: 41306

American (AMR) AF: 0.00 AC: 0 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10530

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.0000140 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
6	-	-	Cystic fibrosis (7)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	CFTR-related disorder (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;C5924204:CFTR-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.5	L
PhyloP100		7.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.96
MVP		0.99
MPC		0.0041
ClinPred		0.86	D
GERP RS		5.4
PromoterAI		0.0023	Neutral
Varity_R		0.93
gMVP		0.96
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs146521846; hg19: chr7-117251848;