rs147623570

Positions:

chr16-87902425-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001739.2(CA5A):c.555G>A(p.Lys185=) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.000152 in 1,594,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CA5A
NM_001739.2 splice_region, synonymous

Scores

Splicing: ADA: 1.000

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1O:1

Conservation

PhyloP100: 5.67

Variant links:

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]

CA5A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 16-87902425-C-T is Pathogenic according to our data. Variant chr16-87902425-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127088.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr16-87902425-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA5A	NM_001739.2 linkuse as main transcript	c.555G>A	p.Lys185=	splice_region_variant, synonymous_variant	4/7	ENST00000649794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Appris
CA5A	ENST00000649794.3 linkuse as main transcript	c.555G>A	p.Lys185=	splice_region_variant, synonymous_variant	4/7	NM_001739.2	P1
CA5A	ENST00000648177.1 linkuse as main transcript	c.436G>A	p.Gly146Arg	missense_variant, splice_region_variant	3/5
CA5A	ENST00000649158.1 linkuse as main transcript	c.555G>A	p.Lys185=	splice_region_variant, synonymous_variant	4/7
CA5A	ENST00000648022.1 linkuse as main transcript	c.555G>A	p.Lys185=	splice_region_variant, synonymous_variant, NMD_transcript_variant	4/8

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251092

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000156

AC:

225

AN:

1442646

Hom.:

Cov.:

AF XY:

0.000181

AC XY:

130

AN XY:

719130

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000196

Gnomad4 OTH exome

AF:

0.0000670

GnomAD4 genome

AF:

0.000112

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000276

Hom.:

Bravo

AF:

0.0000982

ExAC

AF:

0.000123

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency

Pathogenic:1Uncertain:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 06, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 03, 2024	This sequence change affects codon 185 of the CA5A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CA5A protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs147623570, gnomAD 0.03%). This variant has been observed in individual(s) with carbonic anhydrase VA deficiency (PMID: 24530203). ClinVar contains an entry for this variant (Variation ID: 127088). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 4, but is expected to preserve the integrity of the reading-frame (PMID: 24530203). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2021

Published functional studies demonstrate a damaging effect (van Karnebeek et al., 2014; Diez-Fernandez et al., 2016); This variant is associated with the following publications: (PMID: 26913920, 24530203, 25834911) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Benign

0.76

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.27

MetaRNN

Benign

0.32

MutationTaster

Benign

1.0

GERP RS

4.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.89

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.89

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over