11-5948159-A-T

Variant summary

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

The NM_001003443.3(OR56A3):c.813A>T(p.Lys271Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,614,082 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: OR56A3 NM_001003443.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.06

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

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=0.03150797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR56A3	NM_001003443.3	c.813A>T	p.Lys271Asn	missense_variant	3/3	ENST00000641160.1
OR56A3	XM_047426926.1	c.813A>T	p.Lys271Asn	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR56A3	ENST00000641160.1	c.813A>T	p.Lys271Asn	missense_variant	3/3		NM_001003443.3	P1
OR56A3	ENST00000641905.1	c.813A>T	p.Lys271Asn	missense_variant	4/4			P1
OR56A3	ENST00000641878.1	n.402-528A>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000544

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000240 AC: 60 AN: 249754 Hom.: 0 AF XY: 0.000251 AC XY: 34 AN XY: 135468

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000441

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000467 AC: 683 AN: 1461882 Hom.: 1 Cov.: 33 AF XY: 0.000426 AC XY: 310 AN XY: 727242

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000577

Gnomad4 OTH exome AF: 0.000546

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74352

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000544

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000290 Hom.: 0

Bravo AF: 0.000306

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000198 AC: 24

EpiCase AF: 0.000763

EpiControl AF: 0.000593

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

Jan 30, 2024

The c.813A>T (p.K271N) alteration is located in exon 1 (coding exon 1) of the OR56A3 gene. This alteration results from a A to T substitution at nucleotide position 813, causing the lysine (K) at amino acid position 271 to be replaced by an asparagine (N). 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	0.15
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.6
Dann	Benign	0.82
DEOGEN2	Benign	0.043	T;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0087	N
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.032	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.28	N;N;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
Polyphen		0.0030	B;B;B
Vest4		0.10
MutPred		0.35		Loss of methylation at K271 (P = 0.0069);Loss of methylation at K271 (P = 0.0069);Loss of methylation at K271 (P = 0.0069);
MVP		0.17
MPC		0.10
ClinPred		0.027	T
GERP RS		-5.5
Varity_R		0.11
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs201776447; hg19: chr11-5969389;