Genetic Variant OR4D9:p.Thr89Ile (chr11-59515178-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001004711.2(OR4D9):c.266C>T(p.Thr89Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,614,100 control chromosomes in the GnomAD database, including 181 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T89K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.018 ( 81 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 100 hom. )

Consequence

OR4D9
NM_001004711.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.73

Publications

6 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003074348).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR4D9	NM_001004711.2 link	c.266C>T	p.Thr89Ile	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.266C>T	p.Thr89Ile	missense_variant	Exon 3 of 3		NM_001004711.2	ENSP00000493010.1		Q8NGE8
OR4D9	ENST00000641278.1 link	c.266C>T	p.Thr89Ile	missense_variant	Exon 3 of 3			ENSP00000493042.1		Q8NGE8

Frequencies

GnomAD3 genomes

AF:

0.0183

AC:

2791

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0636

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00674

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.00504

AC:

1267

AN:

251292

AF XY:

0.00374

show subpopulations

Gnomad AFR exome

AF:

0.0703

Gnomad AMR exome

AF:

0.00266

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00202

AC:

2959

AN:

1461856

Hom.:

100

Cov.:

AF XY:

0.00176

AC XY:

1279

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0705

AC:

2359

AN:

33458

American (AMR)

AF:

0.00318

AC:

142

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000128

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000103

AC:

114

AN:

1112004

Other (OTH)

AF:

0.00515

AC:

311

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

153

305

458

610

763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0184

AC:

2800

AN:

152244

Hom.:

Cov.:

AF XY:

0.0179

AC XY:

1331

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0637

AC:

2644

AN:

41532

American (AMR)

AF:

0.00667

AC:

102

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68020

Other (OTH)

AF:

0.0175

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

132

264

396

528

660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00627

Hom.:

Bravo

AF:

0.0207

ESP6500AA

AF:

0.0597

AC:

263

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00625

AC:

759

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.088

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.020

T;T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.11

.;.;T

MetaRNN

Benign

0.0031

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.96

L;L;L

PhyloP100

-2.7

PrimateAI

Benign

0.19

PROVEAN

Uncertain

-2.6

.;.;D

REVEL

Benign

0.0070

Sift

Benign

0.035

.;.;D

Sift4G

Benign

0.093

.;.;T

Polyphen

0.0

B;B;B

Vest4

0.062

MVP

0.30

MPC

0.029

ClinPred

0.0070

GERP RS

-6.1

Varity_R

0.068

gMVP

0.086

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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11-59515178-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over