7-117548796-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

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 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -1.15

Publications

12 publications found

Variant links:

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 links:

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

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 VariationId is 193593.

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 link	c.1365G>T	p.Ala455Ala	synonymous_variant	Exon 10 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1 link	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 link	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.:

Cov.:

show subpopulations

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:

AN:

229864

AF XY:

0.0000562

show subpopulations

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:

AN:

1415138

Hom.:

Cov.:

AF XY:

0.0000469

AC XY:

AN XY:

704042

show subpopulations

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

African (AFR)

AF:

0.0000937

AC:

AN:

32018

American (AMR)

AF:

0.0000466

AC:

AN:

42934

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24518

East Asian (EAS)

AF:

0.0000546

AC:

AN:

36624

South Asian (SAS)

AF:

0.0000353

AC:

AN:

84932

European-Finnish (FIN)

AF:

0.000119

AC:

AN:

50466

Middle Eastern (MID)

AF:

0.000183

AC:

AN:

5462

European-Non Finnish (NFE)

AF:

0.0000342

AC:

AN:

1080734

Other (OTH)

AF:

0.000122

AC:

AN:

57450

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.232

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00191

AC:

228

AN:

119204

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

127

AN XY:

57738

show subpopulations

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

African (AFR)

AF:

0.00142

AC:

AN:

32332

American (AMR)

AF:

0.00275

AC:

AN:

11278

Ashkenazi Jewish (ASJ)

AF:

0.000698

AC:

AN:

2866

East Asian (EAS)

AF:

0.00172

AC:

AN:

4062

South Asian (SAS)

AF:

0.00167

AC:

AN:

3588

European-Finnish (FIN)

AF:

0.00800

AC:

AN:

7122

Middle Eastern (MID)

AF:

0.00490

AC:

AN:

204

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

55372

Other (OTH)

AF:

0.00

AC:

AN:

1602

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.236

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0297

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Benign:3

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.

Jul 22, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

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).

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.

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

(source)

DANN

Benign

0.56

PhyloP100

-1.1

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over