7-117587811-C-T

Variant names:

• chr7-117587811-C-T
• rs74597325
• NM_000492.4:c.1657C>T

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1657C>T​(p.Arg553*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000971 in 1,606,458 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: "SCV000883602: Functional characterization indicates that the variant not only leads to severe mRNA depletion (Hamosh 1992), but also causes aberrant splicing (skipping of exon 11) that results in a frameshift (Aznarez 2007)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. R553R) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic practice guideline P:30 O:1
• Conservation: PhyloP100: 1.98
• Publications: 354 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 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000883602: Functional characterization indicates that the variant not only leads to severe mRNA depletion (Hamosh 1992), but also causes aberrant splicing (skipping of exon 11) that results in a frameshift (Aznarez 2007).; SCV000915204: The p.Arg553Ter variant was shown to result in no detectable CFTR mRNA in nasal epithelial cells and lymphocytes derived from a severely affected individual who carried the variant in a compound heterozygous state (Will et al. 1993). RT-PCR studies in patient lymphoblastoid cells lines demonstrated that the p.Arg553Ter variant results in the skipping of exon 11 through the creation of a putative exonic splicing silencer (Aznarez et al. 2007).; SCV000919142: RNA from nasal epithelial cells of a patient with the genotype S549N/R553X showed that <2% of the transcripts were derived from R553X (Hamosh_1991). Additionally, chloride secretion in a rectal biopsy specimens from 3 patients with the genotype deltaF508/R553X found that Cl-secretion was 0% of control, suggesting that R553X is non-functional (Hirtz_2004).
• PP5: Variant 7-117587811-C-T is Pathogenic according to our data. Variant chr7-117587811-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7122.Status of the report is practice_guideline, 4 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.1657C>T	p.Arg553*	stop_gained	Exon 12 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.1657C>T	p.Arg553*	stop_gained	Exon 12 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1657C>T	p.Arg553*	stop_gained	Exon 12 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1657C>T	p.Arg553*	stop_gained	Exon 12 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.0000678 AC: 17 AN: 250780 AF XY: 0.0000885

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: 0.000124

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000942 AC: 137 AN: 1454226 Hom.: 0 Cov.: 27 AF XY: 0.000105 AC XY: 76 AN XY: 724050

African (AFR) AF: 0.0000601 AC: 2 AN: 33266

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.000116 AC: 128 AN: 1105364

Other (OTH) AF: 0.0000499 AC: 3 AN: 60074

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74428

African (AFR) AF: 0.000120 AC: 5 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68008

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000124 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: practice guideline

Pathogenic	VUS	Benign	Condition
15	-	-	Cystic fibrosis (16)
7	-	-	not provided (7)
2	-	-	Bronchiectasis with or without elevated sweat chloride 1 (2)
2	-	-	CFTR-related disorder (2)
2	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (2)
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	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		2.0
Vest4		0.93
GERP RS		4.4
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 22

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74597325; hg19: chr7-117227865;