rs1800112

Positions:

chr7-117610610-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4BP6

The NM_000492.4(CFTR):c.3080T>C(p.Ile1027Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000525 in 1,613,670 control chromosomes in the GnomAD database, including 1 homozygotes. 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. I1027I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00054 ( 1 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14

Conservation

PhyloP100: 7.62

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.40699252).

BP6

Variant 7-117610610-T-C is Benign according to our data. Variant chr7-117610610-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35860.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1, Likely_benign=6}. Variant chr7-117610610-T-C is described in Lovd as [Benign]. Variant chr7-117610610-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3080T>C	p.Ile1027Thr	missense_variant	19/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3080T>C	p.Ile1027Thr	missense_variant	19/27	1	NM_000492.4	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.177+5619A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000381

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000255

AC:

AN:

251050

Hom.:

AF XY:

0.000273

AC XY:

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000502

Gnomad OTH exome

AF:

0.000655

GnomAD4 exome

AF:

0.000540

AC:

789

AN:

1461406

Hom.:

Cov.:

AF XY:

0.000494

AC XY:

359

AN XY:

727008

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000678

Gnomad4 OTH exome

AF:

0.000464

GnomAD4 genome

AF:

0.000381

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000416

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000641

Hom.:

Bravo

AF:

0.000332

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Aug 01, 2023	BP2 -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	CFTR: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 16, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 28, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23523379, 30527892, 31808782, 22137130, 11354633, 19774621, 11729110, 31350925, 27022295, 17035430, 26574590, 8956039, 26911355, 15858154, 16283887, 17825628, 23951356, 23974870, 21520337) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 26, 2023	- -

Cystic fibrosis

Benign:5

Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 15, 2019	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 27, 2015	This alteration is classified as 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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 18, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

CFTR-related disorder

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 31, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 17, 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.81

D;.;.;D;.

Eigen

Benign

0.020

Eigen_PC

Benign

0.067

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.41

T;T;T;T;T

MetaSVM

Uncertain

0.13

MutationAssessor

Uncertain

2.1

M;.;.;.;.

MutationTaster

Benign

0.98

N;N

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.5

N;.;.;N;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.0020

D;.;.;D;.

Sift4G

Uncertain

0.0020

D;.;.;D;.

Polyphen

0.053

B;.;.;.;.

Vest4

0.74

MVP

1.0

MPC

0.0038

ClinPred

0.065

GERP RS

6.2

Varity_R

0.35

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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