chr1-248203187-G-A

Variant names:

• chr1-248203187-G-A
• rs143468114
• NM_001004689.2:c.120G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001004689.2(OR2M3):​c.120G>A​(p.Met40Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,944 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 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: OR2M3 NM_001004689.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.25

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]

ACMG classification

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=0.044168442).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR2M3	NM_001004689.2	c.120G>A	p.Met40Ile	missense_variant	Exon 2 of 2	ENST00000641626.1	NP_001004689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR2M3	ENST00000641626.1	c.120G>A	p.Met40Ile	missense_variant	Exon 2 of 2		NM_001004689.2	ENSP00000492981.1
OR2M3	ENST00000456743.3	c.120G>A	p.Met40Ile	missense_variant	Exon 1 of 1	6		ENSP00000389625.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 151978 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

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

GnomAD3 exomes AF: 0.0000478 AC: 12 AN: 251152 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135728

Gnomad AFR exome AF: 0.000738

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461848 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 727226

Gnomad4 AFR exome AF: 0.000956

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: 0.00

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152096 Hom.: 0 Cov.: 31 AF XY: 0.000175 AC XY: 13 AN XY: 74346

Gnomad4 AFR AF: 0.000651

Gnomad4 AMR AF: 0.000197

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

Bravo AF: 0.000215

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.120G>A (p.M40I) alteration is located in exon 1 (coding exon 1) of the OR2M3 gene. This alteration results from a G to A substitution at nucleotide position 120, causing the methionine (M) at amino acid position 40 to be replaced by an isoleucine (I). 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	0.17
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.33
DANN	Benign	0.53
DEOGEN2	Benign	0.0062	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.16	.;T
M_CAP	Benign	0.00049	T
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.32	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.58	.;N
REVEL	Benign	0.024
Sift	Benign	0.38	.;T
Sift4G	Benign	0.66	.;T
Polyphen		0.0	B;B
Vest4		0.028
MutPred		0.43		Gain of catalytic residue at M40 (P = 0.06);Gain of catalytic residue at M40 (P = 0.06);
MVP		0.13
MPC		0.064
ClinPred		0.013	T
GERP RS		-1.4
Varity_R		0.047
gMVP		0.10

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

Other links and lift over

dbSNP: rs143468114; hg19: chr1-248366489; COSMIC: COSV71758847;