rs146947665

Positions:

chr7-117664847-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_000492.4(CFTR):c.4123C>A(p.His1375Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000206 in 1,613,782 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1375P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 1 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

Conservation

PhyloP100: 3.59

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117664848-A-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.29731584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.4123C>A	p.His1375Asn	missense_variant	25/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.4123C>A	p.His1375Asn	missense_variant	25/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251216

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135756

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:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000220

AC:

322

AN:

1461630

Hom.:

Cov.:

AF XY:

0.000197

AC XY:

143

AN XY:

727150

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000284

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000157

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 13, 2022	This sequence change replaces histidine, which is basic and polar, with asparagine, which is neutral and polar, at codon 1375 of the CFTR protein (p.His1375Asn). This variant is present in population databases (rs146947665, gnomAD 0.01%). This missense change has been observed in individual(s) with chronic pancreatitis and/or CFTR-related metabolic syndrome (PMID: 19202204, 23810505). ClinVar contains an entry for this variant (Variation ID: 53894). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 10, 2022	The p.H1375N variant (also known as c.4123C>A), located in coding exon 25 of the CFTR gene, results from a C to A substitution at nucleotide position 4123. The histidine at codon 1375 is replaced by asparagine, an amino acid with similar properties. This variant was identified in an adult with pancreatic insufficiency and chronic pancreatitis in conjunction with p.F508del; however, the phase was uncertain (Kolesár P et al. Gen. Physiol. Biophys., 2008 Dec;27:299-305). This variant was also reported in a Slovak cystic fibrosis cohort; however, specific genotype and phenotype information was not provided (Soltysova A et al. Clin Respir J, 2018 Mar;12:1197-1206). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 08, 2017	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 13, 2023	The CFTR c.4123C>A; p.His1375Asn variant (rs146947665), is reported in the literature in individuals affected with chronic pancreatitis (Kolesar 2008) or CFTR-related metabolic syndrome (Prach 2013), who also carry the common F508del pathogenic variant on the opposite chromosome. This variant is reported in ClinVar (Variation ID: 53894) and is found in the non-Finnish European population with an allele frequency of 0.016% (20/128962 alleles) in the Genome Aggregation Database. The histidine at codon 1375 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.304). Due to limited information, the clinical significance of the p.His1375Asn variant is uncertain at this time. References: Kolesar P et al. Mutation analysis of the CFTR gene in Slovak cystic fibrosis patients by DHPLC and subsequent sequencing: identification of four novel mutations. Gen Physiol Biophys. 2008 Dec;27(4):299-305. PMID: 19202204 Prach L et al. Novel CFTR variants identified during the first 3 years of cystic fibrosis newborn screening in California. J Mol Diagn. 2013 Sep;15(5):710-22. PMID: 23810505 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2017	- -

CFTR-related disorder

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 24, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 27, 2023	The CFTR c.4123C>A variant is predicted to result in the amino acid substitution p.His1375Asn. This variant has been reported in the compound heterozygous state with the p.Phe508del variant in a patient with chronic pancreatitis without lung disease (Kolesár et al. 2008. PubMed ID: 19202204). This variant has also been identified in the compound heterozygous state with the p.Phe508del variant in patient with CFTR-related metabolic syndrome (Patient 24 in Table 2, Prach et al. 2013. PubMed ID: 23810505), and in a patient with cystic fibrosis from a Slovakian cohort study (Soltysova et al. 2017. PubMed ID: 28544683). This variant has been interpreted by multiple labs in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/53894/). Although we suspect this variant could be pathogenic, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic information. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 22, 2024

Variant summary: CFTR c.4123C>A (p.His1375Asn) results in a conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 1613782 control chromosomes in the gnomAD v4.0.0 database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00021 vs 0.013), allowing no conclusion about variant significance. c.4123C>A has been reported in the literature in at least one individual affected with Cystic Fibrosis (e.g, Zhou_2019), in a pancreatic insufficient individual with chronic pancreatitis but no respiratory involvement (e.g., Kolesar_2008), and an individual diagnosed with CFTR-related metabolic syndrome with normal sweat chloride levels (e.g., Prach_2013); the F508del allele was identified as the second CFTR variant in all of these individuals. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19202204, 23810505, 36409994, 28544683, 31740593). ClinVar contains an entry for this variant (Variation ID: 53894). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Jun 09, 2021

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.89

DEOGEN2

Uncertain

0.49

T;T;.

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.22

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.80

T;T;T

M_CAP

Pathogenic

0.62

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

-0.53

N;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.77

N;N;.

REVEL

Uncertain

0.30

Sift

Benign

0.14

T;T;.

Sift4G

Uncertain

0.055

T;T;.

Polyphen

0.0020

B;.;.

Vest4

0.70

MVP

0.94

MPC

0.0039

ClinPred

0.098

GERP RS

4.9

Varity_R

0.54

gMVP

0.73

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