rs530720914

Variant names:

• chr17-60159483-G-A
• rs530720914
• NM_000717.5:c.*59G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000717.5(CA4):​c.*59G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,563,098 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (13 hom.)
• Consequence: CA4 NM_000717.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: -1.21

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-60159483-G-A is Benign according to our data. Variant chr17-60159483-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445984.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00189 (288/152302) while in subpopulation NFE AF = 0.00307 (209/68024). AF 95% confidence interval is 0.00273. There are 0 homozygotes in GnomAd4. There are 133 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 288 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CA4	NM_000717.5	c.*59G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000300900.9	NP_000708.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CA4	ENST00000300900.9	c.*59G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_000717.5	ENSP00000300900.3
CA4	ENST00000590203.1	c.*59G>A		3_prime_UTR_variant	Exon 4 of 4	3		ENSP00000465837.1
CA4	ENST00000586876.1	n.*178+1037G>A		intron_variant	Intron 5 of 5	2		ENSP00000467465.1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 288 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00309

Gnomad OTH AF: 0.000955

GnomAD4 exome AF: 0.00325 AC: 4583 AN: 1410796 Hom.: 13 Cov.: 24 AF XY: 0.00320 AC XY: 2249 AN XY: 702908

Gnomad4 AFR exome AF: 0.000461 AC: 15 AN: 32520

Gnomad4 AMR exome AF: 0.000657 AC: 28 AN: 42602

Gnomad4 ASJ exome AF: 0.00187 AC: 48 AN: 25606

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 38864

Gnomad4 SAS exome AF: 0.00272 AC: 228 AN: 83760

Gnomad4 FIN exome AF: 0.000562 AC: 26 AN: 46256

Gnomad4 NFE exome AF: 0.00377 AC: 4064 AN: 1078386

Gnomad4 Remaining exome AF: 0.00288 AC: 169 AN: 58616

GnomAD4 genome AF: 0.00189 AC: 288 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.00179 AC XY: 133 AN XY: 74474

Gnomad4 AFR AF: 0.000818 AC: 0.000817819 AN: 0.000817819

Gnomad4 AMR AF: 0.00124 AC: 0.00124199 AN: 0.00124199

Gnomad4 ASJ AF: 0.00432 AC: 0.00432028 AN: 0.00432028

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00166 AC: 0.00165769 AN: 0.00165769

Gnomad4 FIN AF: 0.0000943 AC: 0.0000942507 AN: 0.0000942507

Gnomad4 NFE AF: 0.00307 AC: 0.00307245 AN: 0.00307245

Gnomad4 OTH AF: 0.000945 AC: 0.00094518 AN: 0.00094518

Alfa AF: 0.00281 Hom.: 0

Bravo AF: 0.00210

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

May 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 08, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Retinitis pigmentosa 17 Uncertain:1

Feb 22, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CA4 *59G>A variant (rs530720914) is reported in the medical literature in two families with autosomal dominant retinitis pigmentosa (Yang 2005). The variant is listed in the ClinVar database (Variation ID: 445984) and is found with an overall allele frequency of 0.2% (58/31392 alleles) in the Genome Aggregation Database. This is a variant in the 3' untranslated region in a weakly conserved nucleotide, but patient cells with this variant have a 30% reduction in CA4 RNA transcript compared to control individuals (Yang 2005). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Yang Z et al. Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration. Hum Mol Genet. 2005 Jan 15;14(2):255-65. -

CA4-related disorder Benign:1

Jul 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.071
DANN	Benign	0.62
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs530720914; hg19: chr17-58236844;