rs78769542

Variant names:

• chr7-117611650-G-A
• rs78769542
• NM_000492.4:c.3209G>A
• CFTR p.Arg1070Gln

Your query was ambiguous. Multiple possible variants found:

• chr7-117611650-G-A
• chr7-117611650-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 10P and 5B. PS3 PM1 PM5 PP2 PP3 BP4_Strong BS2_Supporting

The NM_000492.4(CFTR):​c.3209G>A​(p.Arg1070Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,613,422 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). ClinVar reports functional evidence for this variant: "SCV000052172: "These functional differences might be due to the use of different cell lines in different studies and technical backgrounds" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1070W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (6 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: drug response reviewed by expert panel P:26 U:4 O:1
• Conservation: PhyloP100: 9.94
• Publications: 73 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), Laboratory for Molecular Medicine, Myriad Women's Health
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000052172: "These functional differences might be due to the use of different cell lines in different studies and technical backgrounds; however, all of these studies are suggestive of a mild functional impairment for the variant in isolation." PMID:25910067, 1284534, 25087612, 23974870, 8662892, 16049310, 7512860, 30561903, 27171515, 36272381, 19707853, 7529319, 17489851, 23891399, 15880796, 7544320, 29504914, 30930780, 26014425, 27209008, 18467194, 12955726, 11242048, 12007216, 28546993, 18951463, 38388235; SCV001180564: Functional studies have shown that this mutation does not affect protein processing (Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45; Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7), but it was observed to decrease the open probability of the channel (Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45).; SCV001718362: Experimental studies have shown that this missense change affects CFTR function (PMID: 8662892, 8702904, 11242048, 23891399).; SCV005042798: Experimental studies have shown that this missense change affects CFTR function (Van Goor et al., 2014).; SCV004221687: Published functional studies indicate that this variant affects chloride channel gating causing lower open probability of the channel and lower bicarbonate transport (PMID: 8662892 (1996), 11242048 (2001)).; SCV005382382: Experimental studies showed that this variant cause relatively subtle channel defects with functional consequences of a lower open probability of the channel, lower cyclic AMP-stimulated iodide efflux, lower bicarbonate and anion transport (Seibert et al., 1996; Cotten et al., 1996; Krasnov et al., 2008; Sosnay et al., 2013).; SCV000885179: Functional characterization of the variant protein is inconclusive on the expression level of the mature protein (Cotten 1996, Seibert 1996, Sosnay 2013, Van Goor 2014) but indicates an observable decrease in anion transport activity (Choi 2001, Seibert 1996, Sosnay 2013, Van Goor 2014).
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117611650-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 53686.Status of the report is criteria_provided_single_submitter, 1 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: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster, PROVEAN was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.019629806).
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.3209G>A	p.Arg1070Gln	missense	Exon 20 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.177+4579C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3209G>A	p.Arg1070Gln	missense	Exon 20 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.3209G>A	p.Arg1070Gln	missense	Exon 20 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.3122G>A	p.Arg1041Gln	missense	Exon 19 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 151944 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00767

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000610 AC: 153 AN: 250926 AF XY: 0.000782

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000309 AC: 451 AN: 1461360 Hom.: 6 Cov.: 31 AF XY: 0.000432 AC XY: 314 AN XY: 726980

African (AFR) AF: 0.000269 AC: 9 AN: 33454

American (AMR) AF: 0.0000224 AC: 1 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39680

South Asian (SAS) AF: 0.00451 AC: 389 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111738

Other (OTH) AF: 0.000298 AC: 18 AN: 60358

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152062 Hom.: 0 Cov.: 31 AF XY: 0.000471 AC XY: 35 AN XY: 74332

African (AFR) AF: 0.000145 AC: 6 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15258

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2096

Alfa AF: 0.000119 Hom.: 0

Bravo AF: 0.0000945

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	3	-	Cystic fibrosis (12)
4	1	-	not provided (5)
3	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (3)
2	-	-	CFTR-related disorder (2)
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	-	-	Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
1	-	-	Cystic fibrosis;C5924204:CFTR-related disorder (1)
1	-	-	Hereditary pancreatitis (1)
1	-	-	Obstructive azoospermia (1)
1	-	-	Respiratory ciliopathies including non-CF bronchiectasis (1)
-	-	-	ivacaftor response - Efficacy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.020	T
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	0.99	L
PhyloP100		9.9
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.14	N
REVEL	Pathogenic	0.70
Sift	Benign	0.42	T
Sift4G	Pathogenic	0.0	D
PromoterAI		-0.0014	Neutral
Varity_R		0.62
gMVP		0.95
Mutation Taster		=15/85	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs78769542;

hg19: chr7-117251704;