11-59422092-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001001954.2(OR5A2):c.862C>G(p.Pro288Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OR5A2 NM_001001954.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.92

Genes affected

OR5A2 (HGNC:15249): (olfactory receptor family 5 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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR5A2	NM_001001954.2	c.862C>G	p.Pro288Ala	missense_variant	2/2	ENST00000302040.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR5A2	ENST00000302040.6	c.862C>G	p.Pro288Ala	missense_variant	2/2		NM_001001954.2	P1
OR5A2	ENST00000641361.1	c.862C>G	p.Pro288Ala	missense_variant	2/2			P1
OR5A2	ENST00000641673.1	c.862C>G	p.Pro288Ala	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461830 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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 Cov.: 32

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

Feb 05, 2024

The c.862C>G (p.P288A) alteration is located in exon 1 (coding exon 1) of the OR5A2 gene. This alteration results from a C to G substitution at nucleotide position 862, causing the proline (P) at amino acid position 288 to be replaced by an alanine (A). 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	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.044	T;T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	2.0	M;M;M
MutationTaster	Benign	0.53	N
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-7.3	D;.;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.011	D;.;.
Polyphen		0.99	D;D;D
Vest4		0.40
MutPred		0.69		Gain of MoRF binding (P = 0.0564);Gain of MoRF binding (P = 0.0564);Gain of MoRF binding (P = 0.0564);
MVP		0.85
MPC		0.18
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.84
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1565070119; hg19: chr11-59189565;