chr11-4955255-C-G

Variant names:

• chr11-4955255-C-G
• rs751782223
• NM_001004748.1:c.459G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001004748.1(OR51A2):​c.459G>C​(p.Lys153Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000859 in 1,164,274 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: OR51A2 NM_001004748.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.61
• Publications: 0 publications found

Genes affected

OR51A2 (HGNC:14764): (olfactory receptor family 51 subfamily A member 2) 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]

MMP26 (HGNC:14249): (matrix metallopeptidase 26) Proteins of the matrix metalloproteinase (MMP) family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. The encoded preproprotein is proteolytically processed to generate the mature enzyme. This enzyme may degrade collagen type IV, fibronectin, fibrinogen, and beta-casein, and activate matrix metalloproteinase-9 by cleavage. The protein differs from most MMP family members in that it lacks a conserved C-terminal protein domain. The encoded protein may promote cell invasion in multiple human cancers. [provided by RefSeq, May 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR51A2	NM_001004748.1	c.459G>C	p.Lys153Asn	missense_variant	Exon 1 of 1	ENST00000380371.1	NP_001004748.1
MMP26	NM_021801.5	c.-144-32813C>G		intron_variant	Intron 2 of 7	ENST00000380390.6	NP_068573.2
MMP26	NM_001384608.1	c.-152-33015C>G		intron_variant	Intron 2 of 7		NP_001371537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR51A2	ENST00000380371.1	c.459G>C	p.Lys153Asn	missense_variant	Exon 1 of 1	6	NM_001004748.1	ENSP00000369729.1
MMP26	ENST00000380390.6	c.-144-32813C>G		intron_variant	Intron 2 of 7	5	NM_021801.5	ENSP00000369753.1
MMP26	ENST00000300762.2	c.-152-33015C>G		intron_variant	Intron 2 of 7	1		ENSP00000300762.2

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome AF: 8.59e-7 AC: 1 AN: 1164274 Hom.: 0 Cov.: 33 AF XY: 0.00000171 AC XY: 1 AN XY: 583896

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29750

American (AMR) AF: 0.00 AC: 0 AN: 35382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22352

East Asian (EAS) AF: 0.00 AC: 0 AN: 33454

South Asian (SAS) AF: 0.00 AC: 0 AN: 79516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4660

European-Non Finnish (NFE) AF: 0.00000116 AC: 1 AN: 863822

Other (OTH) AF: 0.00 AC: 0 AN: 50204

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 16

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0062	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		-2.6
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.96	D
Vest4		0.093
MutPred		0.64		Loss of ubiquitination at K153 (P = 0.0167);
MVP		0.78
MPC		2.2
ClinPred		0.94	D
GERP RS		-3.2
PromoterAI		-0.029	Neutral
Varity_R		0.25
gMVP		0.37
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs751782223; hg19: chr11-4976485;