rs78655421

Variant names:

• chr7-117530975-G-A
• rs78655421
• NM_000492.4:c.350G>A
• CFTR p.Arg117His

Your query was ambiguous. Multiple possible variants found:

• chr7-117530975-G-A
• chr7-117530975-G-C
• chr7-117530975-G-T

Germline classificationCancer classification (beta)

Variant summary

Our verdict is

Pathogenic

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 16 ACMG points: 16P and 0B. PS3PM5PP3_ModeratePP5_Very_Strong

The NM_000492.4(CFTR):c.350G>A (p.Arg117His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00214 (AC=3,445) in the gnomAD database across 1,613,574 control chromosomes, including 6 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00263. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.52). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★★). ClinVar reports functional evidence for this variant: "SCV000074930: "In a heterologous model system, this missense change decreased CFTR activity by approximately 20-30%." PMID:11242048" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R117L: Likely_pathogenic (ClinVar VariationId 4818539, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R117= (synonymous): Likely_benign (ClinVar VariationId 1560888, 2 stars) This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Cystic fibrosis (cf).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (5 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic practice guideline P:47 O:2
• Conservation: PhyloP100: 9.52
• Publications: 701 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: Myriad Women's Health, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, 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)

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: Well-established functional study supports damaging effect (PS3); SCV000074930: "In a heterologous model system, this missense change decreased CFTR activity by approximately 20-30%." PMID:11242048; SCV000696973: Functional studies indicate that the variant of interest impedes wild type function.; SCV000329245: R117H is a class IV variant which results in defective protein conductance but allows for some residual CFTR function (De Boeck et al., 2014).; SCV000602967: Functional analyses show that p.Arg117His protein has reduced conductance and a decreased occupancy in the open state (LaRusch 2014, Van Goor 2014, Yu 2016), and this variant is found in the general population at an overall allele frequency of 0.1% (398/276670 alleles, 1 homozygote) in the Genome Aggregation Database. PMID: 25033378. PMID: 23891399. PMID: 26846474.; SCV001550195: Functional evidence indicates that the p.R117H variant causes gating defects in CFTR function and results in reduced channel conductance, but retains some residual activity (Yu_2016_PMID:26846474).; SCV000967658: Functional studies have shown that the p.Arg117His variant results in defective protein conductance but retains some residual CFTR function (De Boek 2014).
• PM5: Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R117L: Likely_pathogenic (ClinVar VariationId 4818539, 1 star); Other variants at the same amino acid residue (not pathogenic): p.R117= (synonymous): Likely_benign (ClinVar VariationId 1560888, 2 stars)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
• PP5: ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 4 star(s).

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.350G>A	p.Arg117His	missense	Exon 4 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.350G>A	p.Arg117His	missense	Exon 4 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.350G>A	p.Arg117His	missense	Exon 4 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.350G>A	p.Arg117His	missense	Exon 4 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 231 AN: 152170 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00265

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00149 AC: 373 AN: 250954 AF XY: 0.00148

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00190

Gnomad NFE exome AF: 0.00265

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.00220 AC: 3214 AN: 1461404 Hom.: 5 Cov.: 31 AF XY: 0.00213 AC XY: 1545 AN XY: 727012

African (AFR) AF: 0.000448 AC: 15 AN: 33462

American (AMR) AF: 0.000694 AC: 31 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86240

European-Finnish (FIN) AF: 0.00140 AC: 75 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00271 AC: 3017 AN: 1111726

Other (OTH) AF: 0.00121 AC: 73 AN: 60376

GnomAD4 genome AF: 0.00152 AC: 231 AN: 152170 Hom.: 1 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74340

African (AFR) AF: 0.000579 AC: 24 AN: 41452

American (AMR) AF: 0.000393 AC: 6 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00265 AC: 180 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.00239 Hom.: 1

Bravo AF: 0.00140

EpiCase AF: 0.00169

EpiControl AF: 0.00190

Local populations

ToMMo 61KJPN (+60KJPN MNV) AF: 0.00 AC: 0 AN: 122662

Turkish Variome AF: 0.000531 AC: 2 AN: 5172 Hom.: 0

ABraOM SABE-WGS-1171 AF: 0.000854 AC: 2 AN: 2342 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: practice guideline

Pathogenic	VUS	Benign	Condition
19	-	-	Cystic fibrosis (20)
14	-	-	not provided (14)
3	-	-	CFTR-related disorder (3)
3	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (3)
2	-	-	Congenital bilateral aplasia of vas deferens from CFTR mutation (2)
2	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (2)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Obstructive azoospermia (1)
1	-	-	Pseudomonas aeruginosa, susceptibility to chronic infection by, in cystic fibrosis (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	Benign	0.30
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.18	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		9.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.55
gMVP		0.92
Mutation Taster		=30/70	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs78655421;

hg19: chr7-117171029;

COSMIC: COSV50042918;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar