16-87881815-T-C

Position:

• chr16-87881815-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001367225.1(CA5A):​c.899A>G​(p.His300Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 6/7 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CA5A NM_001367225.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.38

Genes affected

CA5A (HGNC:1377): (carbonic anhydrase 5A) 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. CA VA is localized in the mitochondria and expressed primarily in the liver. It may play an important role in ureagenesis and gluconeogenesis. CA5A gene maps to chromosome 16q24.3 and an unprocessed pseudogene has been assigned to 16p12-p11.2. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070645094).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CA5A	NM_001367225.1	c.899A>G	p.His300Arg	missense_variant	7/7		NP_001354154.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CA5A	ENST00000649158.1	c.899A>G	p.His300Arg	missense_variant	7/7			ENSP00000496993
CA5A	ENST00000648177.1	c.*141A>G		3_prime_UTR_variant	5/5			ENSP00000497626

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Feb 14, 2023

The missense c.899A>G (p.His300Arg) variant in CA5A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.His300Arg variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has not been reported to the ClinVar database. The amino acid His at position 300 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS). In the absence of another reportable variant in CA5A gene, the molecular diagnosis is not confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.13
DANN	Benign	0.29
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.071	T
GERP RS		-1.6

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: rs937413509; hg19: chr16-87915421;