NM_001004748.1:c.511T>G

Variant names:

• chr11-4955203-A-C
• NM_001004748.1:c.511T>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001004748.1(OR51A2):​c.511T>G​(p.Cys171Gly) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 17)
  • Exomes 𝑓: 8.5e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OR51A2 NM_001004748.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18
• 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.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR51A2	NM_001004748.1	c.511T>G	p.Cys171Gly	missense_variant	Exon 1 of 1	ENST00000380371.1	NP_001004748.1
MMP26	NM_021801.5	c.-144-32865A>C		intron_variant	Intron 2 of 7	ENST00000380390.6	NP_068573.2
MMP26	NM_001384608.1	c.-152-33067A>C		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.511T>G	p.Cys171Gly	missense_variant	Exon 1 of 1	6	NM_001004748.1	ENSP00000369729.1
MMP26	ENST00000380390.6	c.-144-32865A>C		intron_variant	Intron 2 of 7	5	NM_021801.5	ENSP00000369753.1
MMP26	ENST00000300762.2	c.-152-33067A>C		intron_variant	Intron 2 of 7	1		ENSP00000300762.2

Frequencies

GnomAD3 genomes Cov.: 17

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.53e-7 AC: 1 AN: 1172008 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 587756

⚠️ 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: 29872

American (AMR) AF: 0.00 AC: 0 AN: 35456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22556

East Asian (EAS) AF: 0.00 AC: 0 AN: 32750

South Asian (SAS) AF: 0.00 AC: 0 AN: 79810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4902

European-Non Finnish (NFE) AF: 0.00000115 AC: 1 AN: 869508

Other (OTH) AF: 0.00 AC: 0 AN: 50218

⚠️ 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.: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.511T>G (p.C171G) alteration is located in exon 1 (coding exon 1) of the OR51A2 gene. This alteration results from a T to G substitution at nucleotide position 511, causing the cysteine (C) at amino acid position 171 to be replaced by a glycine (G). 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	0.14
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Benign	0.82
DEOGEN2	Benign	0.0090	T
Eigen	Benign	0.12
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	4.3	H
PhyloP100		5.2
PROVEAN	Pathogenic	-11	D
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.61		Loss of stability (P = 0.0038);
MVP		0.84
MPC		2.5
ClinPred		1.0	D
GERP RS		1.8
Varity_R		0.78
gMVP		0.39
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr11-4976433;