11-4954915-C-G

Variant names:

• chr11-4954915-C-G
• rs56066301
• NM_001004748.1:c.799G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001004748.1(OR51A2):​c.799G>C​(p.Gly267Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 906,878 control chromosomes in the GnomAD database, including 63,850 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2795 hom., cov: 15)
  • Exomes 𝑓: 0.17 (63850 hom.)
  • Failed GnomAD Quality Control
• Consequence: OR51A2 NM_001004748.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0770
• Publications: 13 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052675903).
• BP6: Variant 11-4954915-C-G is Benign according to our data. Variant chr11-4954915-C-G is described in ClinVar as Benign. ClinVar VariationId is 403274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 63850 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004748.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR51A2	NM_001004748.1	MANE Select	c.799G>C	p.Gly267Arg	missense	Exon 1 of 1	NP_001004748.1	Q8NGJ7
	MMP26	NM_021801.5	MANE Select	c.-144-33153C>G		intron	N/A	NP_068573.2	Q9NRE1
	MMP26	NM_001384608.1		c.-152-33355C>G		intron	N/A	NP_001371537.1	A0A8J8YUH5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR51A2	ENST00000380371.1	TSL:6 MANE Select	c.799G>C	p.Gly267Arg	missense	Exon 1 of 1	ENSP00000369729.1	Q8NGJ7
	MMP26	ENST00000380390.6	TSL:5 MANE Select	c.-144-33153C>G		intron	N/A	ENSP00000369753.1	Q9NRE1
	MMP26	ENST00000300762.2	TSL:1	c.-152-33355C>G		intron	N/A	ENSP00000300762.2	A0A8J8YUH5

Frequencies

GnomAD3 genomes AF: 0.156 AC: 14020 AN: 89938 Hom.: 2794 Cov.: 15

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0937

Gnomad ASJ AF: 0.227

Gnomad EAS AF: 0.193

Gnomad SAS AF: 0.0815

Gnomad FIN AF: 0.125

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.177 AC: 29634 AN: 167744 AF XY: 0.169

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.276

Gnomad EAS exome AF: 0.244

Gnomad FIN exome AF: 0.252

Gnomad NFE exome AF: 0.188

Gnomad OTH exome AF: 0.223

GnomAD4 exome AF: 0.170 AC: 154226 AN: 906878 Hom.: 63850 Cov.: 31 AF XY: 0.173 AC XY: 79279 AN XY: 458052

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

African (AFR) AF: 0.218 AC: 5430 AN: 24898

American (AMR) AF: 0.145 AC: 4411 AN: 30348

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 5583 AN: 17312

East Asian (EAS) AF: 0.290 AC: 8480 AN: 29262

South Asian (SAS) AF: 0.130 AC: 9119 AN: 70228

European-Finnish (FIN) AF: 0.327 AC: 12147 AN: 37110

Middle Eastern (MID) AF: 0.338 AC: 1243 AN: 3678

European-Non Finnish (NFE) AF: 0.152 AC: 99541 AN: 654728

Other (OTH) AF: 0.210 AC: 8272 AN: 39314

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.156 AC: 14032 AN: 90044 Hom.: 2795 Cov.: 15 AF XY: 0.149 AC XY: 6476 AN XY: 43562

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

African (AFR) AF: 0.191 AC: 5548 AN: 28996

American (AMR) AF: 0.0934 AC: 782 AN: 8370

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 431 AN: 1902

East Asian (EAS) AF: 0.193 AC: 609 AN: 3156

South Asian (SAS) AF: 0.0818 AC: 272 AN: 3324

European-Finnish (FIN) AF: 0.125 AC: 650 AN: 5182

Middle Eastern (MID) AF: 0.372 AC: 58 AN: 156

European-Non Finnish (NFE) AF: 0.146 AC: 5475 AN: 37518

Other (OTH) AF: 0.146 AC: 173 AN: 1188

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0691 Hom.: 139

ExAC AF: 0.215 AC: 22742

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.053
DANN	Benign	0.55
DEOGEN2	Benign	0.00032	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.040	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.94	N
PhyloP100		-0.077
PROVEAN	Benign	3.5	N
REVEL	Benign	0.013
Sift	Benign	0.17	T
Sift4G	Benign	0.23	T
Polyphen		0.0	B
Vest4		0.020
MutPred		0.42		Gain of solvent accessibility (P = 0.0037)
MPC		1.3
ClinPred		0.0016	T
GERP RS		0.58
Varity_R		0.042
gMVP		0.062
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs56066301; hg19: chr11-4976145; COSMIC: COSV66748088;