11-6002533-G-A

Variant summary

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

The NM_001005179.4(OR56A4):c.460C>T(p.Arg154Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00052 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000081 (0 hom.)
• Consequence: OR56A4 NM_001005179.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.151

Genes affected

OR56A4 (HGNC:14791): (olfactory receptor family 56 subfamily A member 4) 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]

OR56A3 (HGNC:):

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=0.05854377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR56A4	NM_001005179.4	c.460C>T	p.Arg154Trp	missense_variant	3/3	ENST00000641156.1
OR56A3	XM_047426926.1	c.*469-1187G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR56A4	ENST00000641156.1	c.460C>T	p.Arg154Trp	missense_variant	3/3		NM_001005179.4	P1
OR56A4	ENST00000330728.4	c.616C>T	p.Arg206Trp	missense_variant	1/1
OR56A4	ENST00000641279.1	c.460C>T	p.Arg154Trp	missense_variant	1/1			P1
OR56A4	ENST00000641835.1	c.460C>T	p.Arg154Trp	missense_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251366 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135852

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000814 AC: 119 AN: 1461872 Hom.: 0 Cov.: 35 AF XY: 0.0000798 AC XY: 58 AN XY: 727236

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000519 AC: 79 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74466

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.0000827 Hom.: 0

Bravo AF: 0.000525

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Apr 08, 2022

The c.616C>T (p.R206W) alteration is located in exon 1 (coding exon 1) of the OR56A4 gene. This alteration results from a C to T substitution at nucleotide position 616, causing the arginine (R) at amino acid position 206 to be replaced by a tryptophan (W). 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	0.23
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.14	T;T;T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.0086	N
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.059	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	3.8	H;H;H;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
Polyphen		0.62	P;P;P;.
Vest4		0.67
MVP		0.21
MPC		0.18
ClinPred		0.21	T
GERP RS		-5.8
Varity_R		0.21
gMVP		0.53

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: rs116036052; hg19: chr11-6023763; COSMIC: COSV100417630;