Genetic Variant HAO2:p.Arg50Trp (chr1-119382931-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_016527.4(HAO2):c.148C>T(p.Arg50Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,613,610 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

HAO2
NM_016527.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.45

Variant links:

Genes affected

HAO2 (HGNC:4810): (hydroxyacid oxidase 2) This gene is one of three related genes that have 2-hydroxyacid oxidase activity. The encoded protein localizes to the peroxisome has the highest activity toward the substrate 2-hydroxypalmitate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

HAO2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HAO2	NM_016527.4 link	c.148C>T	p.Arg50Trp	missense_variant	Exon 3 of 8	ENST00000325945.4	NP_057611.1	Q9NYQ3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HAO2	ENST00000325945.4 link	c.148C>T	p.Arg50Trp	missense_variant	Exon 3 of 8	1	NM_016527.4	ENSP00000316339.3	Q9NYQ3-1
HAO2	ENST00000361035.8 link	c.187C>T	p.Arg63Trp	missense_variant	Exon 4 of 9	1		ENSP00000354314.4	Q9NYQ3-2
HAO2	ENST00000622548.4 link	c.148C>T	p.Arg50Trp	missense_variant	Exon 4 of 9	1		ENSP00000483507.1	Q9NYQ3-1
HAO2	ENST00000457318.5 link	c.148C>T	p.Arg50Trp	missense_variant	Exon 3 of 5	3		ENSP00000393955.1	Q5QP02

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000168

AC:

AN:

250452

Hom.:

AF XY:

0.000163

AC XY:

AN XY:

135320

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000579

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.0000546

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000134

AC:

196

AN:

1461270

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

116

AN XY:

726906

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000118

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000154

Hom.:

Bravo

AF:

0.000159

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000157

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.148C>T (p.R50W) alteration is located in exon 4 (coding exon 2) of the HAO2 gene. This alteration results from a C to T substitution at nucleotide position 148, causing the arginine (R) at amino acid position 50 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.31

T;T;.;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

D;D;D;.

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.71

D;D;D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Pathogenic

4.1

.;H;.;H

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-7.8

D;.;D;D

REVEL

Uncertain

0.47

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;.;D

Vest4

0.85, 0.85, 0.87

MVP

0.71

MPC

0.21

ClinPred

0.96

GERP RS

3.8

Varity_R

0.92

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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

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