17-3197815-G-T

Variant names:

• chr17-3197815-G-T
• rs775376889
• NM_012352.3:c.297G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_012352.3(OR1A2):​c.297G>T​(p.Met99Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,609,352 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M99T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: OR1A2 NM_012352.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.94
• Publications: 1 publications found

Genes affected

OR1A2 (HGNC:8180): (olfactory receptor family 1 subfamily A member 2) 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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027129084).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012352.3. 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
	OR1A2	NM_012352.3	MANE Select	c.297G>T	p.Met99Ile	missense	Exon 1 of 1	NP_036484.1	A0A126GVH4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR1A2	ENST00000381951.1	TSL:6 MANE Select	c.297G>T	p.Met99Ile	missense	Exon 1 of 1	ENSP00000371377.1	Q9Y585

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000446 AC: 11 AN: 246680 AF XY: 0.0000526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000268 AC: 39 AN: 1457220 Hom.: 0 Cov.: 43 AF XY: 0.0000359 AC XY: 26 AN XY: 724526

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25760

East Asian (EAS) AF: 0.000806 AC: 32 AN: 39688

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85356

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52982

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5748

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109384

Other (OTH) AF: 0.0000332 AC: 2 AN: 60210

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000286 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.9
DANN	Benign	0.80
DEOGEN2	Benign	0.00071	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.00081	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.97	N
PhyloP100		-3.9
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.021
Sift	Benign	0.094	T
Sift4G	Uncertain	0.049	D
Polyphen		0.0	B
Vest4		0.072
MutPred		0.41		Loss of helix (P = 0.3949)
MVP		0.22
MPC		0.16
ClinPred		0.025	T
GERP RS		0.55
PromoterAI		-0.0040	Neutral
Varity_R		0.058
gMVP		0.048
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs775376889; hg19: chr17-3101109;