rs77325391

Positions:

• chr16-87936316-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001739.2(CA5A):​c.135T>A​(p.Asn45Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,612,282 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (112 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (104 hom.)
• Consequence: CA5A NM_001739.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.93

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021915138).
• BP6: Variant 16-87936316-A-T is Benign according to our data. Variant chr16-87936316-A-T is described in ClinVar as [Benign]. Clinvar id is 380517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CA5A	NM_001739.2	c.135T>A	p.Asn45Lys	missense_variant	1/7	ENST00000649794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CA5A	ENST00000649794.3	c.135T>A	p.Asn45Lys	missense_variant	1/7		NM_001739.2	P1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3385 AN: 151916 Hom.: 112 Cov.: 32

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00899

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00581 AC: 1461 AN: 251304 Hom.: 46 AF XY: 0.00419 AC XY: 569 AN XY: 135834

Gnomad AFR exome AF: 0.0756

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00655

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00231 AC: 3375 AN: 1460244 Hom.: 104 Cov.: 30 AF XY: 0.00201 AC XY: 1460 AN XY: 726564

Gnomad4 AFR exome AF: 0.0757

Gnomad4 AMR exome AF: 0.00452

Gnomad4 ASJ exome AF: 0.00647

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.00519

GnomAD4 genome AF: 0.0223 AC: 3392 AN: 152038 Hom.: 112 Cov.: 32 AF XY: 0.0213 AC XY: 1585 AN XY: 74320

Gnomad4 AFR AF: 0.0767

Gnomad4 AMR AF: 0.00891

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00414 Hom.: 13

Bravo AF: 0.0249

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0726 AC: 319

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00716 AC: 869

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Aug 04, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.052
DANN	Benign	0.71
DEOGEN2	Benign	0.023	T;.;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.31	.;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L;.;.;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N;.;.;.
REVEL	Benign	0.26
Sift	Uncertain	0.026	D;.;.;.
Sift4G	Benign	0.45	T;.;.;.
Polyphen		0.29	B;.;.;B
Vest4		0.11
MutPred		0.63		Gain of methylation at N45 (P = 0.0121);Gain of methylation at N45 (P = 0.0121);Gain of methylation at N45 (P = 0.0121);Gain of methylation at N45 (P = 0.0121);
MVP		0.26
MPC		0.046
ClinPred		0.012	T
GERP RS		-3.4
Varity_R		0.10
gMVP		0.30

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: rs77325391; hg19: chr16-87969922;