11-6002771-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.222C>G(p.Ile74Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,613,834 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: OR56A4 NM_001005179.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.32

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=0.023863763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR56A4	NM_001005179.4	c.222C>G	p.Ile74Met	missense_variant	3/3	ENST00000641156.1
OR56A3	XM_047426926.1	c.*469-949G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR56A4	ENST00000641156.1	c.222C>G	p.Ile74Met	missense_variant	3/3		NM_001005179.4	P1
OR56A4	ENST00000330728.4	c.378C>G	p.Ile126Met	missense_variant	1/1
OR56A4	ENST00000641279.1	c.222C>G	p.Ile74Met	missense_variant	1/1			P1
OR56A4	ENST00000641835.1	c.222C>G	p.Ile74Met	missense_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000219 AC: 55 AN: 250974 Hom.: 0 AF XY: 0.000236 AC XY: 32 AN XY: 135626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000211 AC: 308 AN: 1461630 Hom.: 0 Cov.: 32 AF XY: 0.000209 AC XY: 152 AN XY: 727120

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000219

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74374

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000218

EpiControl AF: 0.000296

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

Aug 04, 2023

The c.378C>G (p.I126M) 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 378, causing the isoleucine (I) at amino acid position 126 to be replaced by a methionine (M). 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	0.072
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.0010
Dann	Benign	0.096
DEOGEN2	Benign	0.013	T;T;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0041	N
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.024	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.85	L;L;L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
Polyphen		0.013	B;B;B;.
Vest4		0.12
MVP		0.19
MPC		0.087
ClinPred		0.014	T
GERP RS		-7.2
Varity_R		0.058
gMVP		0.28

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: rs141110808; hg19: chr11-6024001;