NM_000492.4:c.3873G>C

Variant names:

• chr7-117642593-G-C
• rs121909015
• NM_000492.4:c.3873G>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.3873G>C​(p.Gln1291His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000294 in 1,460,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1291R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: CFTR NM_000492.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 U:1
• Conservation: PhyloP100: 7.59
• Publications: 12 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• 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.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 21 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117642592-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53827.
• 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117642593-G-C is Pathogenic according to our data. Variant chr7-117642593-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 7152.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.3873G>C	p.Gln1291His	missense splice_region	Exon 23 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.65+4758C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3873G>C	p.Gln1291His	missense splice_region	Exon 23 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.3867G>C	p.Gln1289His	missense splice_region	Exon 23 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.3783G>C	p.Gln1261His	missense splice_region	Exon 22 of 26	ENSP00000389119.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000798 AC: 2 AN: 250572 AF XY: 0.00000738

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: 0.0000294 AC: 43 AN: 1460990 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 726774

African (AFR) AF: 0.00 AC: 0 AN: 33444

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111516

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000468 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:4 Uncertain:1

Jan 03, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Apr 01, 1992

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Jul 08, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is present in population databases (rs121909015, gnomAD 0.002%). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1291 of the CFTR protein (p.Gln1291His). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This missense change has been observed in individuals with clinical features of CFTR-related conditions (PMID: 1284466, 7551394, 21388895, 22423042). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in activation of a cryptic splice site in the intron and introduces a premature termination codon (PMID: 1284466). The resulting mRNA is expected to undergo nonsense-mediated decay. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CFTR function (PMID: 31127727). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 7152).

Apr 29, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3873G>C pathogenic mutation (also known as p.Q1291H), located in coding exon 23 of the CFTR gene, results from a G to C substitution at nucleotide position 3873. The amino acid change results in glutamine to histidine at codon 1291, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 23, which makes it likely to have some effect on normal mRNA splicing. Analysis of a biopsy from a pancreatic sufficient individual with mild lung symptoms who was compound heterozygous for p.Q1291H demonstrated normal and aberrant splicing resulting from use of a cryptic site leading to the inclusion of 29 nucleotides in the intron and a predicted premature stop codon (Jones CT et al. Hum. Mol. Genet., 1992 Apr;1:11-7). In addition, this mutation has been reported in several individuals with elevated sweat chloride levels in conjunction with another pathogenic CFTR variant (Jones CT et al. Hum. Mol. Genet., 1992 Apr;1:11-7; Gilfillan A et al. J. Med. Genet., 1998 Feb;35:122-5; Baker MW et al. J. Cyst. Fibros., 2011 Jul;10:278-81) and has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Pediatr. Clin. North Am., 2016 08;63:585-98; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed April 29, 2020). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Mar 02, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Pathogenic:1

Sep 07, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.3873G>C (p.Gln1291His) results in a non-conservative amino acid change in the encoded protein sequence. The variant also alters a conserved nucleotide located to the last nucleotide of exon 20, affecting a canonical splice site and therefore could alter mRNA splicing, leading to a significantly altered protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: 4/5 predict the variant weakens a 5' splicing donor site. At least one publication reported experimental evidence that the variant resulted in both a 'correct' (although altered) splice product, and an incorrectly spliced mRNA from the use of a nearby cryptic splice site (29 bases into the adjacent intron), where the inclusion of the intronic sequence resulted in an in-frame, downstream stop codon (Jones1992). Another functional study demonstrated that the Gln1291His variant protein showed normal processing and trafficking to the plasma membrane, as well as unaltered single channel gating properties in the presence of ATP; however the data suggested the disruption of adenylate kinase-dependent gating that might affect channel activity in airway epithelia (Dong 2015). The variant allele was found at a frequency of 8.1e-06 in 245448 control chromosomes (gnomAD and publications). The variant, c.3873G>C, has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Jones 1992, Dorfman 2010, Baker 2011). These data indicate that the variant is very likely to be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

CFTR-related disorder Pathogenic:1

Mar 02, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Jul 01, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		7.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.91
MutPred		0.98		Loss of MoRF binding (P = 0.1135)
MVP		1.0
MPC		0.017
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.98
gMVP		0.98
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.74		Position offset: 0

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

Other links and lift over

dbSNP: rs121909015; hg19: chr7-117282647;