Genetic Variant OR5H2:p.Leu43Pro (chr3-98283030-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001005482.2(OR5H2):c.128T>C(p.Leu43Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

OR5H2
NM_001005482.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.424

Variant links:

Genes affected

OR5H2 (HGNC:14752): (olfactory receptor family 5 subfamily H member 2) Olfactory receptors interact with odorant molecules in the nose, to initiate a neuronal response that triggers the perception of a smell. The olfactory receptor proteins are members of a large family of G-protein-coupled receptors (GPCR) arising from single coding-exon genes. Olfactory receptors share a 7-transmembrane domain structure with many neurotransmitter and hormone receptors and are responsible for the recognition and G protein-mediated transduction of odorant signals. The olfactory receptor gene family is the largest in the genome. The nomenclature assigned to the olfactory receptor genes and proteins for this organism is independent of other organisms. [provided by RefSeq, Jul 2008]

OR5H2 links:

ENSG00000251088 (HGNC:):

ENSG00000251088 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03206843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR5H2	NM_001005482.2 link	c.128T>C	p.Leu43Pro	missense_variant	Exon 1 of 1	ENST00000355273.3	NP_001005482.2	Q8NGV7
LOC105373999	XR_001740814.2 link	n.71-3142A>G		intron_variant	Intron 1 of 3
LOC105373999	XR_924258.2 link	n.216-5555A>G		intron_variant	Intron 1 of 2
LOC105373999	XR_924259.2 link	n.71-3142A>G		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR5H2	ENST00000355273.3 link	c.128T>C	p.Leu43Pro	missense_variant	Exon 1 of 1	6	NM_001005482.2	ENSP00000347418.3		Q8NGV7

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000239

AC:

AN:

251336

Hom.:

AF XY:

0.000250

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00308

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000146

AC:

214

AN:

1461754

Hom.:

Cov.:

AF XY:

0.000154

AC XY:

112

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00276

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000953

Gnomad4 OTH exome

AF:

0.000248

GnomAD4 genome

AF:

0.000256

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000281

Hom.:

Bravo

AF:

0.000397

ExAC

AF:

0.000239

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.143T>C (p.L48P) alteration is located in exon 1 (coding exon 1) of the OR5H2 gene. This alteration results from a T to C substitution at nucleotide position 143, causing the leucine (L) at amino acid position 48 to be replaced by a proline (P). 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

Uncertain

0.47

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

T;.

Eigen

Benign

-0.026

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.00090

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.8

H;.

PrimateAI

Benign

0.23

PROVEAN

Pathogenic

-6.4

D;D

REVEL

Benign

0.094

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.99

D;.

Vest4

0.49

MVP

0.60

MPC

0.14

ClinPred

0.25

GERP RS

3.0

Varity_R

0.96

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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