rs121434552

Positions:

• chr17-60156653-G-A
• chr17-60156653-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP3_Moderate PP5 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: CA4 NM_000717.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: -6.03

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]

ACMG classification

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	UniProt
CA4	NM_000717.5	c.206G>A	p.Arg69His	missense_variant	3/8	ENST00000300900.9

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000437 AC: 11 AN: 251462 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135920

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: 33 AN: 1461678 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727144

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.: 33

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.0030
DANN	Benign	0.87
DEOGEN2	Benign	0.16	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.47	T
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.86	L
MutationTaster	Benign	3.1e-9	A
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.020	N
REVEL	Uncertain	0.31
Sift	Benign	0.098	T
Sift4G	Benign	0.17	T
Polyphen		0.0020	B
Vest4		0.053
MutPred		0.87		Loss of MoRF binding (P = 0.0045);
MVP		0.39
MPC		0.049
ClinPred		0.079	T
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

Other links and lift over

dbSNP: rs121434552; hg19: chr17-58234014; COSMIC: COSV56282434; COSMIC: COSV56282434;