11-6002245-G-C

Variant summary

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

The NM_001005179.4(OR56A4):c.748C>G(p.Leu250Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000468 in 1,614,134 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 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: OR56A4 NM_001005179.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

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=0.052243173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR56A4	NM_001005179.4	c.748C>G	p.Leu250Val	missense_variant	3/3	ENST00000641156.1
OR56A3	XM_047426926.1	c.*469-1475G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR56A4	ENST00000641156.1	c.748C>G	p.Leu250Val	missense_variant	3/3		NM_001005179.4	P1
OR56A4	ENST00000330728.4	c.904C>G	p.Leu302Val	missense_variant	1/1
OR56A4	ENST00000641279.1	c.748C>G	p.Leu250Val	missense_variant	1/1			P1
OR56A4	ENST00000641835.1	c.748C>G	p.Leu250Val	missense_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000354 AC: 89 AN: 251208 Hom.: 0 AF XY: 0.000390 AC XY: 53 AN XY: 135756

Gnomad AFR exome AF: 0.0000615

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: 0.000278

Gnomad NFE exome AF: 0.000660

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000478 AC: 699 AN: 1461782 Hom.: 0 Cov.: 31 AF XY: 0.000498 AC XY: 362 AN XY: 727184

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.000585

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74500

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000536 Hom.: 0

Bravo AF: 0.000314

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000815 AC: 7

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.00104

EpiControl AF: 0.000889

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

Jun 03, 2022

The c.904C>G (p.L302V) alteration is located in exon 1 (coding exon 1) of the OR56A4 gene. This alteration results from a C to G substitution at nucleotide position 904, causing the leucine (L) at amino acid position 302 to be replaced by a valine (V). 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	0.24
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.034	T;T;T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.088	N
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.052	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.69	N;N;N;.
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.24	T
Polyphen		1.0	D;D;D;.
Vest4		0.12
MVP		0.19
MPC		0.25
ClinPred		0.11	T
GERP RS		2.9
Varity_R		0.056
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs141151096; hg19: chr11-6023475; COSMIC: COSV100417775;