rs121434552

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP3_ModeratePP5BS2

The NM_000717.5(CA4):c.206G>A(p.Arg69His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,461,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R69R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CA4
NM_000717.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: -6.03

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

PP5

Variant 17-60156653-G-A is Pathogenic according to our data. Variant chr17-60156653-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 17609.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}. Variant chr17-60156653-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-60156653-G-A is described in Lovd as [Pathogenic].

BS2

High AC in GnomAdExome4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CA4	NM_000717.5 linkuse as main transcript	c.206G>A	p.Arg69His	missense_variant	3/8	ENST00000300900.9	NP_000708.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CA4	ENST00000300900.9 linkuse as main transcript	c.206G>A	p.Arg69His	missense_variant	3/8	1	NM_000717.5	ENSP00000300900	P1	P22748-1
CA4	ENST00000591725.1 linkuse as main transcript	c.-65G>A		5_prime_UTR_variant	4/5	3		ENSP00000466964
CA4	ENST00000585705.5 linkuse as main transcript	n.299G>A		non_coding_transcript_exon_variant	3/3	3
CA4	ENST00000586876.1 linkuse as main transcript	c.206G>A	p.Arg69His	missense_variant, NMD_transcript_variant	3/6	2		ENSP00000467465		P22748-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251462

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461678

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727144

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 69 of the CA4 protein (p.Arg69His). This variant is present in population databases (rs121434552, gnomAD 0.02%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 17652713, 20450258). ClinVar contains an entry for this variant (Variation ID: 17609). 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 CA4 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CA4 function (PMID: 17652713, 19211803). This variant disrupts the p.Arg69 amino acid residue in CA4. Other variant(s) that disrupt this residue have been observed in individuals with CA4-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 17

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Aug 01, 2007

- -

Retinal dystrophy

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Dept Of Ophthalmology, Nagoya University

Oct 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.0030

DANN

Benign

0.87

DEOGEN2

Benign

0.16

Eigen

Benign

-2.3

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.0097

LIST_S2

Benign

0.47

M_CAP

Benign

0.017

MetaRNN

Pathogenic

0.85

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.86

MutationTaster

Benign

3.1e-9

PrimateAI

Benign

0.25

PROVEAN

Benign

0.020

REVEL

Uncertain

0.31

Sift

Benign

0.098

Sift4G

Benign

0.17

Polyphen

0.0020

Vest4

0.053

MutPred

0.87

Loss of MoRF binding (P = 0.0045);

MVP

0.39

MPC

0.049

ClinPred

0.079

GERP RS

-11

Varity_R

0.26

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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