NM_000492.4:c.1680A>T

Variant names:

• chr7-117590353-A-T
• rs397508267
• NM_000492.4:c.1680A>T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.1680A>T​(p.Arg560Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002715265: This variant has 0% of wild type quantity and function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 08/02/2022) and in one published functional study (Van Goor F et al. J Cyst Fibros, 2014 Jan" and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R560T) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 missense, splice_region
• Scores: Splicing: ADA: 0.005495
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.63
• Publications: 1 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 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002715265: This variant has 0% of wild type quantity and function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 08/02/2022) and in one published functional study (Van Goor F et al. J Cyst Fibros, 2014 Jan;13:29-36).; SCV004803751: The variant results in the loss of mature CFTR and no chloride transport (Van Goor_2014). PMID: 23891399
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 20 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117587833-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 7113.Status of the report is practice_guideline, 4 stars.
• 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, 0.991
• PP5: Variant 7-117590353-A-T is Pathogenic according to our data. Variant chr7-117590353-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1777899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.1680A>T	p.Arg560Ser	missense splice_region	Exon 13 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.1680A>T	p.Arg560Ser	missense splice_region	Exon 13 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1680A>T	p.Arg560Ser	missense splice_region	Exon 13 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889209.1		c.1680A>T	p.Arg560Ser	missense splice_region	Exon 13 of 26	ENSP00000559268.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Cystic fibrosis (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		2.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.99		Loss of methylation at R560 (P = 0.0289)
MVP		1.0
MPC		0.016
ClinPred		1.0	D
GERP RS		3.6
Varity_R		1.0
gMVP		0.99
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0055
dbscSNV1_RF	Benign	0.094
SpliceAI score (max)		0.090		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: rs397508267; hg19: chr7-117230407;