NM_001004703.1:c.863A>G

Variant names:

• chr11-54603136-T-C
• rs11246609
• NM_001004703.1:c.863A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001004703.1(OR4C46):​c.863A>G​(p.Lys288Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.693 in 1,341,650 control chromosomes in the GnomAD database, including 334,783 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K288N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.68 (35130 hom., cov: 26)
  • Exomes 𝑓: 0.70 (299653 hom.)
• Consequence: OR4C46 NM_001004703.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.24

Genes affected

OR4C46 (HGNC:31271): (olfactory receptor family 4 subfamily C member 46) 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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007537931).
• BP6: Variant 11-54603136-T-C is Benign according to our data. Variant chr11-54603136-T-C is described in ClinVar as [Benign]. Clinvar id is 768448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR4C46	NM_001004703.1	c.863A>G	p.Lys288Arg	missense_variant	Exon 1 of 1	ENST00000328188.1	NP_001004703.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR4C46	ENST00000328188.1	c.863A>G	p.Lys288Arg	missense_variant	Exon 1 of 1	6	NM_001004703.1	ENSP00000329056.1

Frequencies

GnomAD3 genomes AF: 0.676 AC: 101807 AN: 150528 Hom.: 35107 Cov.: 26

Gnomad AFR AF: 0.562

Gnomad AMI AF: 0.737

Gnomad AMR AF: 0.778

Gnomad ASJ AF: 0.808

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.769

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.691

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.718

GnomAD3 exomes AF: 0.723 AC: 148623 AN: 205508 Hom.: 56706 AF XY: 0.726 AC XY: 80339 AN XY: 110660

Gnomad AFR exome AF: 0.547

Gnomad AMR exome AF: 0.810

Gnomad ASJ exome AF: 0.792

Gnomad EAS exome AF: 0.767

Gnomad SAS exome AF: 0.763

Gnomad FIN exome AF: 0.641

Gnomad NFE exome AF: 0.712

Gnomad OTH exome AF: 0.753

GnomAD4 exome AF: 0.696 AC: 828496 AN: 1191004 Hom.: 299653 Cov.: 26 AF XY: 0.700 AC XY: 418388 AN XY: 597848

Gnomad4 AFR exome AF: 0.533

Gnomad4 AMR exome AF: 0.806

Gnomad4 ASJ exome AF: 0.798

Gnomad4 EAS exome AF: 0.793

Gnomad4 SAS exome AF: 0.753

Gnomad4 FIN exome AF: 0.657

Gnomad4 NFE exome AF: 0.685

Gnomad4 OTH exome AF: 0.711

GnomAD4 genome AF: 0.676 AC: 101871 AN: 150646 Hom.: 35130 Cov.: 26 AF XY: 0.676 AC XY: 49680 AN XY: 73518

Gnomad4 AFR AF: 0.562

Gnomad4 AMR AF: 0.779

Gnomad4 ASJ AF: 0.808

Gnomad4 EAS AF: 0.764

Gnomad4 SAS AF: 0.770

Gnomad4 FIN AF: 0.644

Gnomad4 NFE AF: 0.706

Gnomad4 OTH AF: 0.722

Alfa AF: 0.700 Hom.: 6963

Bravo AF: 0.682

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_noAF	Benign	-0.74
CADD	Benign	15
DANN	Benign	0.038
DEOGEN2	Benign	0.0010	T
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0075	T
PROVEAN	Benign	2.8	N
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.20
gMVP		0.60

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: rs11246609; hg19: chr11-51516144; COSMIC: COSV60218239;