7-117540231-G-T

Variant names:

• chr7-117540231-G-T
• rs397508137
• NM_000492.4:c.1001G>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.1001G>T​(p.Arg334Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,892 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: "SCV001581099: Experimental studies have shown that this missense change affects CFTR function (PMID:12679372, 15130785, 17673962, 30046002)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R334Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11 O:1
• Conservation: PhyloP100: 7.60
• Publications: 26 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: SCV001581099: Experimental studies have shown that this missense change affects CFTR function (PMID: 12679372, 15130785, 17673962, 30046002).; SCV001474475: Functional assays show that residue 334 is critical for ion binding, and variants at this codon, including p.Arg334Leu, disrupt channel function (Enquist 2009, Gong 2003, Gong 2004, Raraigh 2018, Zhou 2007).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 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 chr7-117540231-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53159.
• 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, 0.981
• PP5: Variant 7-117540231-G-T is Pathogenic according to our data. Variant chr7-117540231-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 53160.Status of the report is reviewed_by_expert_panel, 3 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.1001G>T	p.Arg334Leu	missense	Exon 8 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.1001G>T	p.Arg334Leu	missense	Exon 8 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1001G>T	p.Arg334Leu	missense	Exon 8 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1001G>T	p.Arg334Leu	missense	Exon 8 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152044 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74262

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41376

American (AMR) AF: 0.00 AC: 0 AN: 15252

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
7	-	-	Cystic fibrosis (8)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	CFTR-related disorder (1)
1	-	-	Cystic fibrosis;C5924204:CFTR-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.6
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.73
Sift	Benign	0.046	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.93		Loss of MoRF binding (P = 0.0315)
MVP		0.97
MPC		0.0048
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.79
gMVP		0.93
Mutation Taster		=2/98	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

Other links and lift over

dbSNP: rs397508137; hg19: chr7-117180285;