7-117642574-C-T

Position:

chr7-117642574-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_StrongBP6BS2_Supporting

The NM_000492.4(CFTR):c.3854C>T(p.Ala1285Val) variant causes a missense change. The variant allele was found at a frequency of 0.000317 in 1,613,382 control chromosomes in the GnomAD database, including 2 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 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 2 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:4O:1

Conservation

PhyloP100: 5.72

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:

ENSG00000083622 (HGNC:):

ENSG00000083622 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a domain ABC transporter 2 (size 233) in uniprot entity CFTR_HUMAN there are 28 pathogenic changes around while only 3 benign (90%) in NM_000492.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0143978).

BP6

Variant 7-117642574-C-T is Benign according to our data. Variant chr7-117642574-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53823.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6, not_provided=1, Benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 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/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3854C>T	p.Ala1285Val	missense_variant	23/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3854C>T	p.Ala1285Val	missense_variant	23/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00684

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000662

AC:

166

AN:

250762

Hom.:

AF XY:

0.000930

AC XY:

126

AN XY:

135506

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00530

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000327

AC:

478

AN:

1461170

Hom.:

Cov.:

AF XY:

0.000477

AC XY:

347

AN XY:

726892

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00516

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000217

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00685

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000198

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.000675

AC:

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:1Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 11, 2023	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 provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 09, 2017	- -

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 06, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in the heterozygous state in an individual with chronic pancreatitis in published literature (PMID: 33097431); This variant is associated with the following publications: (PMID: 19324992, 30146269, 32906206, 32784480, 33138774, 29261177, 34145097, 33097431, 21254931) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 29, 2022	The frequency of this variant in the general population, 0.0053 (162/30594 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with congenital bilateral absence of the vas deferens (CBAVD) (PMID: 21254931 (2011), 34145097 (2020)) and in an individual with pancreatitis (PMID: 33097431 (2020)). The variant has also been reported in carrier screenings (PMID: 19324992 (2009), 29261177 (2018), 30146269 (2019), 32784480 (2020), 32906206 (2020), 33138774 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 12, 2022

Variant summary: CFTR c.3854C>T (p.Ala1285Val) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 250862 control chromosomes (gnomAD), predominantly at a frequency of 0.0053 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is somewhat lower than the maximum expected for a pathogenic variant in CFTR causing Congenital Bilateral Absence of the Vas Deferens (CBAVD) (0.013), allowing no conclusion about variant significance. c.3854C>T has been reported in the literature in at least two Asian Indian individuals affected with CBAVD, however no second (likely) pathogenic variant was specified in these cases (Sachdeva 2011, Gaikwad_2020). The variant was also found during carrier screening in homozygosity in an Asian Indian (Schwartz_2009) and an Australian individual (Archibald_2017), but no phenotype information was provided. These reports do not provide unequivocal conclusions about association of the variant with CBAVD. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters have assessed the variant since 2014: three classified the variant as of uncertain significance, one as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Mar 01, 2023

The missense c.3854C>T (p.Ala1285Val) variant in CFTR gene has been reported previously in heterozygous state in individual(s) affected with SPINK1-associated Chronic Pancreatitis (Jones et al., 2020). This variant is reported with the allele frequency of 0.06% in the gnomAD Exomes. This variant has been reported to the ClinVar database with varying interpretation: Benign / Likely Benign / Uncertain Significance (multiple submitters). The amino acid Ala at position 1285 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala1285Val in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted as damaging by SIFT. SPINK1 carriers with co-occurring mutations in CFTR exhibited prominent fibrosis of the pancreas and only focal intralobular and/or extralobular lipomatous infiltration into the pancreatic parenchyma. For these reasons, this variant has been classified as Uncertain Significance. -

CFTR-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.37

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.80

D;D;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.81

T;T;T

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.014

T;T;T

MetaSVM

Uncertain

0.79

MutationAssessor

Benign

0.56

N;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.1

N;N;.

REVEL

Pathogenic

0.79

Sift

Benign

0.042

D;D;.

Sift4G

Uncertain

0.013

D;D;.

Polyphen

1.0

D;.;.

Vest4

0.89

MutPred

0.68

Gain of methylation at K1284 (P = 0.0334);.;.;

MVP

1.0

MPC

0.0042

ClinPred

0.093

GERP RS

5.3

Varity_R

0.84

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over