Genetic Variant OR2A7:p.Pro128His (chr7-144259246-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001005328.2(OR2A7):c.383C>A(p.Pro128His) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 17)

Exomes 𝑓: 0.000014 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

OR2A7
NM_001005328.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.80

Variant links:

Genes affected

OR2A7 (HGNC:8234): (olfactory receptor family 2 subfamily A member 7) 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]

OR2A7 links:

ARHGEF34P (HGNC:38086): (Rho guanine nucleotide exchange factor 34, pseudogene)

ARHGEF34P links:

ARHGEF35-AS1 (HGNC:41292): (ARHGEF35 antisense RNA 1)

ARHGEF35-AS1 links:

ENSG00000284644 (HGNC:):

ENSG00000284644 links:

OR2A1-AS1 (HGNC:49168): (OR2A1 antisense RNA 1)

OR2A1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR2A7	NM_001005328.2 link	c.383C>A	p.Pro128His	missense_variant	Exon 2 of 2	ENST00000641841.1	NP_001005328.1	Q96R45A0A126GWD8
ARHGEF34P	NR_033942.1 link	n.3954C>A		non_coding_transcript_exon_variant	Exon 13 of 13
ARHGEF35-AS1	NR_126022.1 link	n.494-21226G>T		intron_variant	Intron 2 of 4
OR2A1-AS1	NR_126023.1 link	n.608-19503C>A		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR2A7	ENST00000641841.1 link	c.383C>A	p.Pro128His	missense_variant	Exon 2 of 2		NM_001005328.2	ENSP00000493320.1		Q96R45

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

120052

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000352

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000135

AC:

AN:

811900

Hom.:

Cov.:

AF XY:

0.00000727

AC XY:

AN XY:

412902

show subpopulations

Gnomad4 AFR exome

AF:

0.000529

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:

0.00

Gnomad4 OTH exome

AF:

0.0000262

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000916

AC:

AN:

120134

Hom.:

Cov.:

AF XY:

0.0000531

AC XY:

AN XY:

56486

show subpopulations

Gnomad4 AFR

AF:

0.000351

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.383C>A (p.P128H) alteration is located in exon 1 (coding exon 1) of the OR2A7 gene. This alteration results from a C to A substitution at nucleotide position 383, causing the proline (P) at amino acid position 128 to be replaced by a histidine (H). 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

0.20

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.063

T;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.012

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Benign

-0.99

MutationAssessor

Pathogenic

3.6

H;H

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-8.8

.;D

REVEL

Benign

0.25

Sift

Pathogenic

0.0

.;D

Sift4G

Pathogenic

0.0

.;D

Polyphen

1.0

D;D

Vest4

0.82

MutPred

0.62

Gain of catalytic residue at P128 (P = 0.0565);Gain of catalytic residue at P128 (P = 0.0565);

MVP

0.64

ClinPred

0.99

GERP RS

2.1

Varity_R

0.68

gMVP

0.35

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