chr7-117535348-T-G

Variant names:

• chr7-117535348-T-G
• rs397508782
• NM_000492.4:c.680T>G

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.680T>G​(p.Leu227Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L227L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 7.58
• Publications: 11 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)

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• 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, 0.989
• PP5: Variant 7-117535348-T-G is Pathogenic according to our data. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535348-T-G is described in CliVar as Pathogenic. Clinvar id is 54040.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.680T>G	p.Leu227Arg	missense_variant	Exon 6 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.680T>G	p.Leu227Arg	missense_variant	Exon 6 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

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

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:2

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

CFTR-related disorder Pathogenic:1

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;.;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Uncertain	2.1	M;.;.;.;M
PhyloP100		7.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-4.1	D;.;.;D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;.;.;D;.
Sift4G	Pathogenic	0.0	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.95
MutPred		0.96		Gain of methylation at L227 (P = 0.001);Gain of methylation at L227 (P = 0.001);Gain of methylation at L227 (P = 0.001);.;Gain of methylation at L227 (P = 0.001);
MVP		1.0
MPC		0.012
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.97
Mutation Taster		=4/96	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: rs397508782; hg19: chr7-117175402;