NM_000492.4:c.3897A>G

Variant names:

• chr7-117652865-A-G
• rs1800131
• NM_000492.4:c.3897A>G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6 BP7 BS2_Supporting

The NM_000492.4(CFTR):​c.3897A>G​(p.Thr1299Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,577,400 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:18
• Conservation: PhyloP100: 0.174

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 7-117652865-A-G is Benign according to our data. Variant chr7-117652865-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 93154.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=5, Uncertain_significance=1}. Variant chr7-117652865-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.174 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3897A>G	p.Thr1299Thr	synonymous_variant	Exon 24 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3897A>G	p.Thr1299Thr	synonymous_variant	Exon 24 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.000960 AC: 146 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00169

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00104 AC: 260 AN: 249246 Hom.: 1 AF XY: 0.00117 AC XY: 157 AN XY: 134658

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000729

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000662

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.00162 AC: 2313 AN: 1425136 Hom.: 3 Cov.: 26 AF XY: 0.00161 AC XY: 1142 AN XY: 710888

Gnomad4 AFR exome AF: 0.000275

Gnomad4 AMR exome AF: 0.000924

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000590

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.00198

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.000959 AC: 146 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74458

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00169

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00153 Hom.: 0

Bravo AF: 0.00117

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:18

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 24, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CFTR c.3897A>G (p.Thr1299Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 141/121634 control chromosomes (1 homozygote) at a frequency of 0.0011592, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603), however the homozygous occurrence does suggest a benign role of the variant. In the literature, the variant is reported in both control and patient populations across multiple ethnicities. However, genotypic information of the patients carrying the variant is not clearly specified in publications, and most of them classify it as a 'polymorphism.' One LabCorp specimen carries F508del (DV) and c.1021T>C (DV) (phase of the variants unknown) and the clinical representation of the pt is reported to be CF. In addition, UMD classifies the variant as a polymorphism that is reported in 5 patients (CF or CBAVD), each carrying two other deleterious variants. Although phase of the two deleterious variants is not reported for every patient, UMD cites 2 CF patients that carry p.Lys710X in cis with p.Thr1299Thr. Thus, we have a unequivocal evidence of the presence of deleterious variant(s) in cis with this silent variant in CF patients, suggesting a notion that it is not causally related to these phenotypes and is likely to be a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as benign. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 10, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: BP4, BP7 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Thr1299Thr in exon 24 of CFTR: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 0.1% (10/8600) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs1800131). -

Jan 11, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis Benign:4

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jul 06, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2018

CFTR-France

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

the variant does not result in CFTR-RD neither -

CFTR-related disorder Uncertain:1 Benign:2

Mar 21, 2018

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2021

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary pancreatitis Benign:1

Apr 21, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.6
DANN	Benign	0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs1800131; hg19: chr7-117292919;