7-117548796-G-T

Position:

• chr7-117548796-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000492.4(CFTR):​c.1365G>T​(p.Ala455=) 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).

• 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:):

ACMG classification

Verdict is Likely_benign. Variant got -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: {Likely_benign=4, Benign=1, Uncertain_significance=2}.
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1365G>T	p.Ala455=	synonymous_variant	10/27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.222-6257C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1365G>T	p.Ala455=	synonymous_variant	10/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 225 AN: 119138 Hom.: 0 Cov.: 32 FAILED QC

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

GnomAD3 exomes AF: 0.0000479 AC: 11 AN: 229864 Hom.: 0 AF XY: 0.0000562 AC XY: 7 AN XY: 124496

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 SAS 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

Gnomad4 AMR exome AF: 0.0000466

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000546

Gnomad4 SAS exome AF: 0.0000353

Gnomad4 FIN exome AF: 0.000119

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.000122

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

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.000698

Gnomad4 EAS AF: 0.00172

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.00800

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.00

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

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 03, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 30, 2022	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 16, 2015	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). -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 12, 2016

- -

CFTR-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.13
DANN	Benign	0.56

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;