11-58422868-T-C

Variant names:

• chr11-58422868-T-C
• rs147336729
• NM_001005566.3:c.394A>G

Variant summary

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

The NM_001005566.3(OR5B2):​c.394A>G​(p.Thr132Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00019 in 1,613,706 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: OR5B2 NM_001005566.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.31

Genes affected

OR5B2 (HGNC:8323): (olfactory receptor family 5 subfamily B 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=0.012981087).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR5B2	NM_001005566.3	c.394A>G	p.Thr132Ala	missense_variant	Exon 3 of 3	ENST00000641342.2	NP_001005566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR5B2	ENST00000641342.2	c.394A>G	p.Thr132Ala	missense_variant	Exon 3 of 3		NM_001005566.3	ENSP00000493419.1
OR5B2	ENST00000302581.2	c.394A>G	p.Thr132Ala	missense_variant	Exon 1 of 1	6		ENSP00000303076.2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000335 AC: 84 AN: 250788 Hom.: 0 AF XY: 0.000376 AC XY: 51 AN XY: 135496

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.000168

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000195 AC: 285 AN: 1461568 Hom.: 1 Cov.: 34 AF XY: 0.000215 AC XY: 156 AN XY: 727070

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000896

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00104

Gnomad4 FIN exome AF: 0.00125

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74352

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000818 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000305 AC: 37

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.394A>G (p.T132A) alteration is located in exon 1 (coding exon 1) of the OR5B2 gene. This alteration results from a A to G substitution at nucleotide position 394, causing the threonine (T) at amino acid position 132 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	Benign	0.069
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	13
DANN	Benign	0.68
DEOGEN2	Benign	0.0082	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.47	.;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.7	.;D
REVEL	Benign	0.016
Sift	Uncertain	0.017	.;D
Sift4G	Benign	0.10	.;T
Polyphen		0.011	B;B
Vest4		0.026
MVP		0.10
MPC		0.0051
ClinPred		0.033	T
GERP RS		1.4
Varity_R		0.24
gMVP		0.13

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: rs147336729; hg19: chr11-58190341;