rs397508210

Positions:

chr7-117559521-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_000492.4(CFTR):c.1450C>T(p.His484Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000807 in 1,611,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 7.44

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:):

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1450C>T	p.His484Tyr	missense_variant	11/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730
CFTR-AS1	NR_149084.1 linkuse as main transcript	n.221+1212G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1450C>T	p.His484Tyr	missense_variant	11/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251326

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000617

AC:

AN:

1459252

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000301

Hom.:

Bravo

AF:

0.0000718

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2022	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 484 of the CFTR protein (p.His484Tyr). This variant is present in population databases (rs397508210, gnomAD 0.009%). This missense change has been observed in individual(s) with congenital absence of vas deferens (CAVD), but a second possibly causative variant was not identified (PMID: 10875853). ClinVar contains an entry for this variant (Variation ID: 53257). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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	Jan 21, 2022	The p.H484Y variant (also known as c.1450C>T), located in coding exon 11 of the CFTR gene, results from a C to T substitution at nucleotide position 1450. The histidine at codon 484 is replaced by tyrosine, an amino acid with similar properties. This alteration was identified in an individual with congenital absence of the vas deferens (CAVD) (Casals T et al. Hum Reprod, 2000 Jul;15:1476-83). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 07, 2018	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with congenital absence of the vas deferens (CAVD) in published literature (Casals et al., 2000; Feng et al., 2022); This variant is associated with the following publications: (PMID: 25735457, 35913788, 10875853, 26277102, 18556774) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 08, 2017	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 02, 2023

Variant summary: CFTR c.1450C>T (p.His484Tyr) results in a conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251326 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1450C>T has been reported in the literature in an individual affected with Congenital Bilateral Absence of the Vas Deferens without an identified second allele (Casals_2000). These reports do not provide unequivocal conclusions about association of the variant with Congenital Bilateral Absence Of The Vas Deferens. 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: 10875853, 18556774, 25735457, 26277102). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. 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

Center of Genomic medicine, Geneva, University Hospital of Geneva

Apr 27, 2018

This recessive variant was identified in a patient with repetitive pancreatitis. The patient harbours also a second variant (see below) in this gene in compound heterozygosity -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;.;.;T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

-0.38

N;.;.;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.1

N;.;.;N;.

REVEL

Pathogenic

0.75

Sift

Uncertain

0.022

D;.;.;D;.

Sift4G

Uncertain

0.026

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.96

MutPred

0.83

Loss of disorder (P = 0.0429);.;.;.;.;

MVP

0.98

MPC

0.0040

ClinPred

0.49

GERP RS

5.5

Varity_R

0.74

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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