17-3278208-C-T

Position:

• chr17-3278208-C-T

Variant summary

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

The NM_002551.5(OR3A2):​c.710G>A​(p.Arg237Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0006 in 1,614,228 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00063 (1 hom.)
• Consequence: OR3A2 NM_002551.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.253

Genes affected

OR3A2 (HGNC:8283): (olfactory receptor family 3 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

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=0.05404061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR3A2	NM_002551.5	c.710G>A	p.Arg237Gln	missense_variant	5/5		NP_002542.4
OR3A2	XM_047436157.1	c.734G>A	p.Arg245Gln	missense_variant	7/7		XP_047292113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR3A2	ENST00000573901.3	c.710G>A	p.Arg237Gln	missense_variant	5/5	3		ENSP00000516654.1
OR3A2	ENST00000641164.1	c.710G>A	p.Arg237Gln	missense_variant	1/1			ENSP00000493039.1
OR3A2	ENST00000642052.1	c.710G>A	p.Arg237Gln	missense_variant	2/2			ENSP00000493441.1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152222 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.000661

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000347 AC: 87 AN: 250990 Hom.: 0 AF XY: 0.000376 AC XY: 51 AN XY: 135802

Gnomad AFR exome AF: 0.0000624

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000705

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000626 AC: 915 AN: 1461888 Hom.: 1 Cov.: 32 AF XY: 0.000587 AC XY: 427 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000799

Gnomad4 OTH exome AF: 0.000281

GnomAD4 genome AF: 0.000354 AC: 54 AN: 152340 Hom.: 0 Cov.: 30 AF XY: 0.000322 AC XY: 24 AN XY: 74508

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000528 Hom.: 0

Bravo AF: 0.000321

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000412 AC: 50

EpiCase AF: 0.000382

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2024

The c.728G>A (p.R243Q) alteration is located in exon 1 (coding exon 1) of the OR3A2 gene. This alteration results from a G to A substitution at nucleotide position 728, causing the arginine (R) at amino acid position 243 to be replaced by a glutamine (Q). 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	0.092
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.025	.;.;T
Eigen	Benign	0.010
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.80	.;T;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.054	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	.;.;L
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-3.1	.;.;D
REVEL	Benign	0.034
Sift	Uncertain	0.0010	.;.;D
Sift4G	Uncertain	0.016	.;.;D
Polyphen		1.0	.;.;D
Vest4		0.098
MVP		0.42
MPC		1.5
ClinPred		0.22	T
GERP RS		1.8
Varity_R		0.22
gMVP		0.093

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs201997751; hg19: chr17-3181502; COSMIC: COSV68694985; COSMIC: COSV68694985;