17-60150074-C-T

Position:

chr17-60150074-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP5BS2

The NM_000717.5(CA4):c.40C>T(p.Arg14Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000167 in 1,599,366 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CA4
NM_000717.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: -0.734

Variant links:

Genes affected

CA4 (HGNC:1375): (carbonic anhydrase 4) Carbonic anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide. They participate in a variety of biological processes, including respiration, calcification, acid-base balance, bone resorption, and the formation of aqueous humor, cerebrospinal fluid, saliva, and gastric acid. They show extensive diversity in tissue distribution and in their subcellular localization. This gene encodes a glycosylphosphatidyl-inositol-anchored membrane isozyme expressed on the luminal surfaces of pulmonary (and certain other) capillaries and proximal renal tubules. Its exact function is not known; however, it may have a role in inherited renal abnormalities of bicarbonate transport. [provided by RefSeq, Jul 2008]

CA4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM1

In a signal_peptide (size 17) in uniprot entity CAH4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000717.5

PP5

Variant 17-60150074-C-T is Pathogenic according to our data. Variant chr17-60150074-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17607.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}. Variant chr17-60150074-C-T is described in Lovd as [Pathogenic].

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA4	NM_000717.5 linkuse as main transcript	c.40C>T	p.Arg14Trp	missense_variant	1/8	ENST00000300900.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA4	ENST00000300900.9 linkuse as main transcript	c.40C>T	p.Arg14Trp	missense_variant	1/8	1	NM_000717.5	P1	P22748-1
CA4	ENST00000591725.1 linkuse as main transcript	c.-319C>T		5_prime_UTR_variant	1/5	3
CA4	ENST00000585705.5 linkuse as main transcript	n.133C>T		non_coding_transcript_exon_variant	1/3	3
CA4	ENST00000586876.1 linkuse as main transcript	c.40C>T	p.Arg14Trp	missense_variant, NMD_transcript_variant	1/6	2			P22748-2

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152248

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:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000248

AC:

AN:

221764

Hom.:

AF XY:

0.000242

AC XY:

AN XY:

123816

show subpopulations

Gnomad AFR exome

AF:

0.000151

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:

0.000876

Gnomad NFE exome

AF:

0.000392

Gnomad OTH exome

AF:

0.000536

GnomAD4 exome

AF:

0.000170

AC:

246

AN:

1447000

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

115

AN XY:

720318

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000612

Gnomad4 NFE exome

AF:

0.000177

Gnomad4 OTH exome

AF:

0.000300

GnomAD4 genome

AF:

0.000138

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000124

Hom.:

Bravo

AF:

0.0000756

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CA4-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2024

The CA4 c.40C>T variant is predicted to result in the amino acid substitution p.Arg14Trp. This variant has been reported to be causative for autosomal dominant retinitis pigmentosa in three unrelated families (Rebello et al. 2004. PubMed ID: 15090652; Yang et al. 2005. PubMed ID: 15563508). In one family the variant segregated with disease in 13 affected individuals across three generations (Yang et al. 2005. PubMed ID: 15563508). This variant is reported in 0.081% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 07, 2018

The CA4 c.40C>T (p.Arg14Trp) variant has been reported in at least 37 individuals from three large families with autosomal dominant retinitis pigmentosa. The variant was shown to segregate with disease in at least two of these families (Rebello et al. 2004; Yang et al. 2005). The p.Arg14Trp variant was absent from 36 unaffected family members and 1200 control chromosomes (Rebello et al. 2004; Yang et al. 2005), but is reported at a frequency of 0.00072 in the European (non-Finnish) population of the Exome Aggregation Consortium. Rebello et al. (2004) showed a reduction of CA4 secretion in transfected COS-7 cells carrying the p.Arg14Trp variant, but secretion was comparable to wildtype in a second study that used transfected HEK293 cells (Yang et al. 2005). However, Yang et al. (2005) showed that the p.Arg14Trp variant decreased binding of the CA4 protein to NBC1, thereby disrupting NBC1-mediated recovery of intracellular pH after acid-load. Based on the collective evidence, the p.Arg14Trp variant is classified as pathogenic for autosomal dominant retinitis pigmentosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Retinitis pigmentosa 17

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jan 15, 2005

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 14 of the CA4 protein (p.Arg14Trp). This variant is present in population databases (rs104894559, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 15090652, 15563508). ClinVar contains an entry for this variant (Variation ID: 17607). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CA4 function (PMID: 15090652, 15295099, 15563508, 20626030). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.58

M_CAP

Pathogenic

0.56

MetaRNN

Uncertain

0.65

MetaSVM

Benign

-0.52

MutationAssessor

Benign

2.0

MutationTaster

Benign

3.4e-12

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.36

Sift

Benign

0.030

Sift4G

Uncertain

0.028

Polyphen

0.99

Vest4

0.22

MVP

0.75

MPC

2.5

ClinPred

0.065

GERP RS

-0.83

Varity_R

0.064

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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