chr7-117535278-G-A

Position:

chr7-117535278-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000492.4(CFTR):c.610G>A(p.Ala204Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,612,144 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A204S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.87

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 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, 14 uncertain in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.610G>A	p.Ala204Thr	missense_variant	6/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.610G>A	p.Ala204Thr	missense_variant	6/27	1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000200

AC:

AN:

150328

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000491

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000795

AC:

AN:

251424

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135884

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:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461816

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727210

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000200

AC:

AN:

150328

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73432

show subpopulations

Gnomad4 AFR

AF:

0.0000491

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:

0.0000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000865

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 04, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 22, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 204 of the CFTR protein (p.Ala204Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with cystic fibrosis (PMID: 19017867). ClinVar contains an entry for this variant (Variation ID: 555386). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 19017867). 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 19, 2023

Variant summary: CFTR c.610G>A (p.Ala204Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251424 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.610G>A has been reported in the literature in individuals affected with Cystic Fibrosis (Mutesa_2009) . These report(s) do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. One publication reports weak expression and altered glycosylation (Mutesa_2009), however, does not allow convincing conclusions about the variant effect. The following publication have been ascertained in the context of this evaluation (PMID: 19017867). Two 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Uncertain

0.73

D;.;.;D;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

D;D;D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.74

D;D;D;D;D

MetaSVM

Benign

-0.36

MutationAssessor

Benign

0.88

L;.;.;.;L

MutationTaster

Benign

0.85

D;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.9

N;.;.;N;.

REVEL

Uncertain

0.53

Sift

Benign

0.17

T;.;.;T;.

Sift4G

Benign

0.60

T;.;.;T;.

Polyphen

0.062

B;.;.;.;.

Vest4

0.74

MutPred

0.86

Loss of catalytic residue at A204 (P = 0.3132);Loss of catalytic residue at A204 (P = 0.3132);Loss of catalytic residue at A204 (P = 0.3132);.;Loss of catalytic residue at A204 (P = 0.3132);

MVP

0.99

MPC

0.0043

ClinPred

0.26

GERP RS

4.6

Varity_R

0.59

gMVP

0.82

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