11-4955578-T-C

Position:

• chr11-4955578-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001004748.1(OR51A2):​c.136A>G​(p.Thr46Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,253,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: OR51A2 NM_001004748.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.25

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08646855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR51A2	NM_001004748.1	c.136A>G	p.Thr46Ala	missense_variant	1/1	ENST00000380371.1	NP_001004748.1
MMP26	NM_021801.5	c.-144-32490T>C		intron_variant		ENST00000380390.6	NP_068573.2
MMP26	NM_001384608.1	c.-152-32692T>C		intron_variant			NP_001371537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR51A2	ENST00000380371.1	c.136A>G	p.Thr46Ala	missense_variant	1/1		NM_001004748.1	ENSP00000369729	P1
MMP26	ENST00000380390.6	c.-144-32490T>C		intron_variant		5	NM_021801.5	ENSP00000369753	P1
MMP26	ENST00000300762.2	c.-152-32692T>C		intron_variant		1		ENSP00000300762

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD3 exomes AF: 0.00000857 AC: 2 AN: 233392 Hom.: 0 AF XY: 0.00000792 AC XY: 1 AN XY: 126298

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 6 AN: 1253350 Hom.: 0 Cov.: 31 AF XY: 0.00000635 AC XY: 4 AN XY: 629934

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000491

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000559

GnomAD4 genome Cov.: 20

ExAC AF: 0.00000826 AC: 1

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

Feb 23, 2023

The c.136A>G (p.T46A) alteration is located in exon 1 (coding exon 1) of the OR51A2 gene. This alteration results from a A to G substitution at nucleotide position 136, causing the threonine (T) at amino acid position 46 to be replaced by an alanine (A). 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	0.087
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.91
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N;N
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.048
Sift	Benign	0.097	T
Sift4G	Benign	0.076	T
Polyphen		0.051	B
Vest4		0.026
MutPred		0.44		Loss of catalytic residue at F49 (P = 0.1733);
MVP		0.50
MPC		1.2
ClinPred		0.13	T
GERP RS		2.9
Varity_R		0.12
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs773341269; hg19: chr11-4976808;