Genetic Variant OR10G4:p.His94Leu (chr11-124015855-A-T) – 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_001004462.2(OR10G4):c.281A>T(p.His94Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,611,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

OR10G4
NM_001004462.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.31

Variant links:

Genes affected

OR10G4 (HGNC:14809): (olfactory receptor family 10 subfamily G member 4) 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]

OR10G4 links:

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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=0.04622677).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR10G4	NM_001004462.2 link	c.281A>T	p.His94Leu	missense_variant	Exon 2 of 2	ENST00000641722.1	NP_001004462.1	Q8NGN3A0A126GWS5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR10G4	ENST00000641722.1 link	c.281A>T	p.His94Leu	missense_variant	Exon 2 of 2		NM_001004462.2	ENSP00000493036.1		Q8NGN3
OR10G4	ENST00000641521.1 link	c.281A>T	p.His94Leu	missense_variant	Exon 3 of 3			ENSP00000493354.1		Q8NGN3

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151526

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:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

247874

Hom.:

AF XY:

0.00000744

AC XY:

AN XY:

134348

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:

0.00

Gnomad NFE exome

AF:

0.00000896

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460086

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726088

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:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151526

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

73970

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:

0.0000589

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 29, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.281A>T (p.H94L) alteration is located in exon 1 (coding exon 1) of the OR10G4 gene. This alteration results from a A to T substitution at nucleotide position 281, causing the histidine (H) at amino acid position 94 to be replaced by a leucine (L). 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

0.089

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.42

DANN

Benign

0.71

DEOGEN2

Benign

0.0073

T;T;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.031

.;.;T

M_CAP

Benign

0.0027

MetaRNN

Benign

0.046

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.79

N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.7

.;.;N

REVEL

Benign

0.016

Sift

Benign

0.26

.;.;T

Sift4G

Benign

0.28

.;.;T

Polyphen

0.087

B;B;B

Vest4

0.19

MutPred

0.28

Loss of catalytic residue at H94 (P = 0.0076);Loss of catalytic residue at H94 (P = 0.0076);Loss of catalytic residue at H94 (P = 0.0076);

MVP

0.18

MPC

0.62

ClinPred

0.078

GERP RS

-3.1

Varity_R

0.11

gMVP

0.11

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

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