Genetic Variant NM_001004689.2:c.232G>A (chr1-248203299-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001004689.2(OR2M3):c.232G>A(p.Val78Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,613,980 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. V78L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0072 ( 16 hom., cov: 31)

Exomes 𝑓: 0.00087 ( 8 hom. )

Consequence

OR2M3
NM_001004689.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.95

Publications

4 publications found

Variant links:

Genes affected

OR2M3 (HGNC:8269): (olfactory receptor family 2 subfamily M member 3) 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]

OR2M3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0049291253).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0072 (1096/152130) while in subpopulation AFR AF = 0.0237 (984/41486). AF 95% confidence interval is 0.0225. There are 16 homozygotes in GnomAd4. There are 536 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004689.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR2M3	NM_001004689.2	MANE Select	c.232G>A	p.Val78Ile	missense	Exon 2 of 2	NP_001004689.1	Q8NG83

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR2M3	ENST00000641626.1	MANE Select	c.232G>A	p.Val78Ile	missense	Exon 2 of 2	ENSP00000492981.1	Q8NG83
	OR2M3	ENST00000456743.3	TSL:6	c.232G>A	p.Val78Ile	missense	Exon 1 of 1	ENSP00000389625.1	Q8NG83

Frequencies

GnomAD3 genomes

AF:

0.00717

AC:

1090

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0236

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00505

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.00214

AC:

537

AN:

251328

AF XY:

0.00162

show subpopulations

Gnomad AFR exome

AF:

0.0268

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000317

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.000870

AC:

1272

AN:

1461850

Hom.:

Cov.:

AF XY:

0.000831

AC XY:

604

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.0236

AC:

791

AN:

33474

American (AMR)

AF:

0.00190

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.000104

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00330

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000205

AC:

228

AN:

1111990

Other (OTH)

AF:

0.00230

AC:

139

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

193

290

386

483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00720

AC:

1096

AN:

152130

Hom.:

Cov.:

AF XY:

0.00721

AC XY:

536

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.0237

AC:

984

AN:

41486

American (AMR)

AF:

0.00504

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000623

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10592

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68004

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

144

192

240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.00837

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0225

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00242

AC:

294

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.85

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0059

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.1

PhyloP100

-3.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.79

REVEL

Benign

0.058

Sift

Benign

0.062

Sift4G

Benign

0.13

Polyphen

0.58

Vest4

0.040

MVP

0.20

MPC

0.059

ClinPred

0.0065

GERP RS

2.4

PromoterAI

-0.014

Neutral

(source)

Varity_R

0.038

gMVP

0.037

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over