11-5947843-T-C

Variant names:

• chr11-5947843-T-C
• rs201306705
• NM_001003443.3:c.497T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001003443.3(OR56A3):​c.497T>C​(p.Leu166Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L166I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: OR56A3 NM_001003443.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31
• Publications: 2 publications found

Genes affected

OR56A3 (HGNC:14786): (olfactory receptor family 56 subfamily A 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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR56A3	NM_001003443.3	c.497T>C	p.Leu166Pro	missense_variant	Exon 3 of 3	ENST00000641160.1	NP_001003443.2
OR56A3	XM_047426926.1	c.497T>C	p.Leu166Pro	missense_variant	Exon 3 of 6		XP_047282882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR56A3	ENST00000641160.1	c.497T>C	p.Leu166Pro	missense_variant	Exon 3 of 3		NM_001003443.3	ENSP00000493059.1
OR56A3	ENST00000641905.1	c.497T>C	p.Leu166Pro	missense_variant	Exon 4 of 4			ENSP00000493319.1
OR56A3	ENST00000641878.1	n.402-844T>C		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000116 AC: 29 AN: 250206 AF XY: 0.000103

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000246 AC: 360 AN: 1461888 Hom.: 0 Cov.: 36 AF XY: 0.000227 AC XY: 165 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000305 AC: 339 AN: 1112010

Other (OTH) AF: 0.000281 AC: 17 AN: 60396

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74364

African (AFR) AF: 0.0000483 AC: 2 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000209 Hom.: 0

Bravo AF: 0.000151

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000461 AC: 2

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.497T>C (p.L166P) alteration is located in exon 1 (coding exon 1) of the OR56A3 gene. This alteration results from a T to C substitution at nucleotide position 497, causing the leucine (L) at amino acid position 166 to be replaced by a proline (P). 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	Benign	-0.0093	T
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.77	.;.;T
M_CAP	Benign	0.0061	T
MetaRNN	Uncertain	0.67	D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Pathogenic	4.0	H;H;H
PhyloP100		1.3
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-6.8	.;.;D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	.;.;D
Sift4G	Pathogenic	0.0	.;.;D
Polyphen		1.0	D;D;D
Vest4		0.42
MVP		0.76
MPC		0.25
ClinPred		0.28	T
GERP RS		5.1
Varity_R		0.93
gMVP		0.82
Mutation Taster		=56/44	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: rs201306705; hg19: chr11-5969073;