17-60150011-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000717.5(CA4):c.-24G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00683 in 1,597,832 control chromosomes in the GnomAD database, including 437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (200 hom., cov: 31)
  • Exomes 𝑓: 0.0044 (237 hom.)
• Consequence: CA4 NM_000717.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.02

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-60150011-G-C is Benign according to our data. Variant chr17-60150011-G-C is described in ClinVar as [Benign]. Clinvar id is 324225.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-60150011-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA4	NM_000717.5	c.-24G>C		5_prime_UTR_variant	1/8	ENST00000300900.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA4	ENST00000300900.9	c.-24G>C		5_prime_UTR_variant	1/8	1	NM_000717.5	P1
CA4	ENST00000591725.1	c.-382G>C		5_prime_UTR_variant	1/5	3
CA4	ENST00000585705.5	n.70G>C		non_coding_transcript_exon_variant	1/3	3
CA4	ENST00000586876.1	c.-24G>C		5_prime_UTR_variant, NMD_transcript_variant	1/6	2

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4499 AN: 152236 Hom.: 200 Cov.: 31

Gnomad AFR AF: 0.0960

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0139

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0370

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0224

GnomAD3 exomes AF: 0.00989 AC: 2219 AN: 224422 Hom.: 73 AF XY: 0.00794 AC XY: 990 AN XY: 124712

Gnomad AFR exome AF: 0.0925

Gnomad AMR exome AF: 0.00655

Gnomad ASJ exome AF: 0.00105

Gnomad EAS exome AF: 0.0335

Gnomad SAS exome AF: 0.00220

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000536

Gnomad OTH exome AF: 0.00853

GnomAD4 exome AF: 0.00443 AC: 6409 AN: 1445478 Hom.: 237 Cov.: 30 AF XY: 0.00404 AC XY: 2910 AN XY: 719622

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.00753

Gnomad4 ASJ exome AF: 0.00100

Gnomad4 EAS exome AF: 0.0382

Gnomad4 SAS exome AF: 0.00202

Gnomad4 FIN exome AF: 0.0000231

Gnomad4 NFE exome AF: 0.000306

Gnomad4 OTH exome AF: 0.0101

GnomAD4 genome AF: 0.0296 AC: 4507 AN: 152354 Hom.: 200 Cov.: 31 AF XY: 0.0290 AC XY: 2164 AN XY: 74506

Gnomad4 AFR AF: 0.0960

Gnomad4 AMR AF: 0.0138

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0369

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.0222

Alfa AF: 0.0153 Hom.: 12

Bravo AF: 0.0333

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	11
Dann	Benign	0.63

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: rs345191; hg19: chr17-58227372;