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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 17

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet

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 VariationId is 445984.
• 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 passed quality control check.
• BS2: High AC in GnomAd4 at 288 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000717.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA4	NM_000717.5	MANE Select	c.*59G>A		3_prime_UTR	Exon 8 of 8	NP_000708.1
	CA4	NR_137422.2		n.1060G>A		non_coding_transcript_exon	Exon 8 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CA4	ENST00000300900.9	TSL:1 MANE Select	c.*59G>A		3_prime_UTR	Exon 8 of 8	ENSP00000300900.3
	CA4	ENST00000904866.1		c.*59G>A		3_prime_UTR	Exon 9 of 9	ENSP00000574925.1
	CA4	ENST00000904870.1		c.*59G>A		3_prime_UTR	Exon 8 of 8	ENSP00000574929.1

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

African (AFR) AF: 0.000461 AC: 15 AN: 32520

American (AMR) AF: 0.000657 AC: 28 AN: 42602

Ashkenazi Jewish (ASJ) AF: 0.00187 AC: 48 AN: 25606

East Asian (EAS) AF: 0.00 AC: 0 AN: 38864

South Asian (SAS) AF: 0.00272 AC: 228 AN: 83760

European-Finnish (FIN) AF: 0.000562 AC: 26 AN: 46256

Middle Eastern (MID) AF: 0.00119 AC: 5 AN: 4186

European-Non Finnish (NFE) AF: 0.00377 AC: 4064 AN: 1078386

Other (OTH) 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

African (AFR) AF: 0.000818 AC: 34 AN: 41574

American (AMR) AF: 0.00124 AC: 19 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00307 AC: 209 AN: 68024

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00281 Hom.: 0

Bravo AF: 0.00210

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	CA4-related disorder (1)
-	1	-	Retinitis pigmentosa 17 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.071
DANN	Benign	0.62
PhyloP100		-1.2
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

Other links and lift over

dbSNP: rs530720914; hg19: chr17-58236844;