Genetic Variant OR4D9:p.Cys254Ser (chr11-59515673-G-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001004711.2(OR4D9):c.761G>C(p.Cys254Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00774 in 1,614,090 control chromosomes in the GnomAD database, including 84 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0048 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 80 hom. )

Consequence

OR4D9
NM_001004711.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.327

Variant links:

Genes affected

OR4D9 (HGNC:15178): (olfactory receptor family 4 subfamily D member 9) 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]

OR4D9 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0072151423).

BP6

Variant 11-59515673-G-C is Benign according to our data. Variant chr11-59515673-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2641813.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR4D9	NM_001004711.2 link	c.761G>C	p.Cys254Ser	missense_variant	Exon 3 of 3	ENST00000641962.1	NP_001004711.1	Q8NGE8A0A126GVP8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR4D9	ENST00000641962.1 link	c.761G>C	p.Cys254Ser	missense_variant	Exon 3 of 3		NM_001004711.2	ENSP00000493010.1		Q8NGE8
OR4D9	ENST00000641278.1 link	c.761G>C	p.Cys254Ser	missense_variant	Exon 3 of 3			ENSP00000493042.1		Q8NGE8

Frequencies

GnomAD3 genomes

AF:

0.00481

AC:

731

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00828

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00463

AC:

1164

AN:

251422

Hom.:

AF XY:

0.00467

AC XY:

634

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00295

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00238

Gnomad FIN exome

AF:

0.00106

Gnomad NFE exome

AF:

0.00799

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00804

AC:

11756

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00785

AC XY:

5707

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00128

Gnomad4 AMR exome

AF:

0.00295

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00252

Gnomad4 FIN exome

AF:

0.00157

Gnomad4 NFE exome

AF:

0.00974

Gnomad4 OTH exome

AF:

0.00729

GnomAD4 genome

AF:

0.00480

AC:

731

AN:

152202

Hom.:

Cov.:

AF XY:

0.00437

AC XY:

325

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00209

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00828

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00654

Hom.:

Bravo

AF:

0.00488

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00966

AC:

ExAC

AF:

0.00460

AC:

558

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00714

EpiControl

AF:

0.00688

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

OR4D9: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.015

T;T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.67

.;.;T

M_CAP

Benign

0.0036

MetaRNN

Benign

0.0072

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.26

N;N;N

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-7.1

.;.;D

REVEL

Benign

0.11

Sift

Benign

0.16

.;.;T

Sift4G

Benign

0.062

.;.;T

Polyphen

0.47

P;P;P

Vest4

0.19

MutPred

0.51

Loss of catalytic residue at P253 (P = 0.0148);Loss of catalytic residue at P253 (P = 0.0148);Loss of catalytic residue at P253 (P = 0.0148);

MVP

0.49

MPC

0.068

ClinPred

0.047

GERP RS

3.3

Varity_R

0.49

gMVP

0.14

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