7-117548796-G-T

Variant names:

• chr7-117548796-G-T
• rs79074685
• NM_000492.4:c.1365G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000492.4(CFTR):​c.1365G>T​(p.Ala455Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A455A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -1.15

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-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 7-117548796-G-T is Benign according to our data. Variant chr7-117548796-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193593.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4, Benign=1}.
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1365G>T	p.Ala455Ala	synonymous_variant	Exon 10 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.222-6257C>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1365G>T	p.Ala455Ala	synonymous_variant	Exon 10 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 225 AN: 119138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000698

Gnomad EAS AF: 0.00147

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.00800

Gnomad MID AF: 0.00476

Gnomad NFE AF: 0.00139

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000479 AC: 11 AN: 229864 AF XY: 0.0000562

Gnomad AFR exome AF: 0.0000695

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000147

Gnomad NFE exome AF: 0.0000689

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000431 AC: 61 AN: 1415138 Hom.: 0 Cov.: 35 AF XY: 0.0000469 AC XY: 33 AN XY: 704042

Gnomad4 AFR exome AF: 0.0000937 AC: 3 AN: 32018

Gnomad4 AMR exome AF: 0.0000466 AC: 2 AN: 42934

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 24518

Gnomad4 EAS exome AF: 0.0000546 AC: 2 AN: 36624

Gnomad4 SAS exome AF: 0.0000353 AC: 3 AN: 84932

Gnomad4 FIN exome AF: 0.000119 AC: 6 AN: 50466

Gnomad4 NFE exome AF: 0.0000342 AC: 37 AN: 1080734

Gnomad4 Remaining exome AF: 0.000122 AC: 7 AN: 57450

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00191 AC: 228 AN: 119204 Hom.: 0 Cov.: 32 AF XY: 0.00220 AC XY: 127 AN XY: 57738

Gnomad4 AFR AF: 0.00142 AC: 0.00142274 AN: 0.00142274

Gnomad4 AMR AF: 0.00275 AC: 0.00274871 AN: 0.00274871

Gnomad4 ASJ AF: 0.000698 AC: 0.000697837 AN: 0.000697837

Gnomad4 EAS AF: 0.00172 AC: 0.00172329 AN: 0.00172329

Gnomad4 SAS AF: 0.00167 AC: 0.00167224 AN: 0.00167224

Gnomad4 FIN AF: 0.00800 AC: 0.00800337 AN: 0.00800337

Gnomad4 NFE AF: 0.00141 AC: 0.00140865 AN: 0.00140865

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

⚠️ The allele balance in gnomAD4 Genomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0297 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Benign:3

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 03, 2017

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. -

not specified Benign:2

Jun 07, 2018

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.1365G>T (p.Ala455Ala) alters a non-conserved nucleotide resulting in a synonymous change in exon 10 of the gene. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0071 in 238136 control chromosomes (in gnomAD). The observed variant frequency in the African (0.02640) and European Finnish (0.02228) subpopulations was roughly 2-fold of the expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.013). Furthermore, the variant allele was indicated to be found with an even higher occurrence in the Japanese control population (in HGVD); i.e. with a frequency of 0.1348 (including 19 homozygotes), that would suggest this variant is likely a benign polymorphism. However, CFTR exon 10 and its flanking regions are known to have sequence identity with similar sequences in the human genome (that are located on several other chromosomes), therefore variants described in this exon could be variations observed in ectopic similar sequences. Previous reports also suggested that several variants described in exon 10 and its flanking regions may in fact be ectopic variations (PMID: 23261175, 25956447). As the technology utilized for genomic databases does not rule out pseudogene interference in this region, these data may not be reliable for assessing variant frequency. To our knowledge, no occurrence of c.1365G>T in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Another variant, c.1365G>A, that affects the same nucleotide and leads to the same codon effect (p.Ala455Ala) was classified as likely benign by our laboratory. Based on the evidence outlined above, the variant of interest was classified as likely benign. -

Feb 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala455Ala in exon 10 of CFTR: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 62/85992 of chromosomes across several diverse populations by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs79074685). -

CFTR-related disorder Uncertain:1

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1

Jan 12, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.13
DANN	Benign	0.56
Mutation Taster		=97/3	polymorphism

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

Publications

LitVar

Other links and lift over

dbSNP: rs79074685; hg19: chr7-117188850; COSMIC: COSV50042423;