7-117614713-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_000492.4(CFTR):c.3468G>T(p.Leu1156Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000379 in 1,602,446 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1156L) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00040 ( 7 hom. )

Consequence

CFTR
NM_000492.4 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 6.67

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 4 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, 12 uncertain in NM_000492.4

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3468G>T	p.Leu1156Phe	missense_variant, splice_region_variant	21/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3468G>T	p.Leu1156Phe	missense_variant, splice_region_variant	21/27	1	NM_000492.4	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.177+1516C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

151970

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:

0.00520

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000132

AC:

AN:

250770

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135530

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000401

AC:

581

AN:

1450358

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

291

AN XY:

722280

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0145

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000100

GnomAD4 genome

AF:

0.000178

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00521

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000119

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.000198

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 29, 2024	The c.3468G>T variant (also known as p.L1156F), located in coding exon 21 of the CFTR gene, results from a G to T substitution at nucleotide position 3468. The amino acid change results in leucine to phenylalanine at codon 1156, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 21, which makes it likely to have some effect on normal mRNA splicing. This variant has been reported in multiple Japanese individuals with idiopathic, familial, hereditary, and alcoholic pancreatitis, including one individual with alcoholic pancreatitis who was homozygous for this alteration (Nakano E, Dig. Dis. Sci. 2015 May; 60(5):1297-307; Kondo S, Am. J. Physiol. Gastrointest. Liver Physiol. 2015 Aug; 309(4):G260-9). This nucleotide position is highly conserved in available vertebrate species, and this amino acid position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 29, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 19, 2022

Variant summary: CFTR c.3468G>T (p.Leu1156Phe) involves the alteration of a conserved nucleotide located in the last position of exon 21. 3/4 splice prediction tools predict a slight weakening of a canonical 5' splice donor site. However, these predictions have yet to be confirmed by functional studies. In the absence of splice change the variant would result in a non-conservative amino acid change that is located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251130 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.0016 in the gnomAD database. This frequency is lower than estimated for a pathogenic variant in CFTR causing CFTR-related diseases (0.0016 vs. 0.013), allowing no conclusion about variant significance. The variant has been reported in two publications to be statistically associated with idiopathic and alcoholic chronic pancreatitis in Japanese patients (example, Kondo 2015, Nakano 2015, Iso_2019), however the sample size in these case-control studies was small and the authors did not adjust for the effect of other likely pathogenic or pathogenic CFTR, SPINK1, and CTRC variants that were found in co-occurrence in several patients in these cohorts. Another study reports this variant as a non-informative genotype (second allele or zygosity not specified) in at-least two Chinese individuals, one with CAVD and another with oligoasthenospermia (example, Li_2022). These report(s) do not provide unequivocal conclusions about association of the variant with CFTR-Related Diseases. At least one publication reports experimental evidence evaluating an impact on protein function, showing that CFTR expression, Cl- current, HCO3- and Cl- transport was not different from wild-type in cells expressing the variant of interest, however, Cl-/HCO3- exchange activity was reduced to 30% of the wild-type levels and two patients had higher than normal sweat chloride levels (Kondo 2015). The variant of interest in combination with a benign polymorphism (V470M) had reduced CFTR expression (to 60-70%), CFTR-mediated HCO3-/Cl- transport (to 50-60%) and the Cl-/HCO3-exchange activity (to 2030%) compared to wild-type (Kondo 2015). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=1), VUS (n=4). Based on all these conflicting evidence outlined above, the variant was classified as a VUS, until more definitive functional and clinical studies become available. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 04, 2021

- -

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

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Pathogenic

0.17

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;.;.;T;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.026

T;T;T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.2

M;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.73

N;.;.;N;.

REVEL

Uncertain

0.60

Sift

Benign

0.16

T;.;.;T;.

Sift4G

Uncertain

0.0020

D;.;.;D;.

Polyphen

0.99

D;.;.;.;.

Vest4

0.73

MutPred

0.38

Loss of stability (P = 0.0994);.;.;.;.;

MVP

1.0

MPC

0.0052

ClinPred

0.29

GERP RS

5.9

Varity_R

0.32

gMVP

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.84

SpliceAI score (max)

0.71

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.71

Position offset: 0

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