11-4954915-C-G

Position:

• chr11-4954915-C-G

Variant summary

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

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. 13/19 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

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 Benign. Variant got -20 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 id is 403274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR51A2	NM_001004748.1	c.799G>C	p.Gly267Arg	missense_variant	1/1	ENST00000380371.1
MMP26	NM_021801.5	c.-144-33153C>G		intron_variant		ENST00000380390.6
MMP26	NM_001384608.1	c.-152-33355C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR51A2	ENST00000380371.1	c.799G>C	p.Gly267Arg	missense_variant	1/1		NM_001004748.1	P1
MMP26	ENST00000380390.6	c.-144-33153C>G		intron_variant		5	NM_021801.5	P1
MMP26	ENST00000300762.2	c.-152-33355C>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 14020 AN: 89938 Hom.: 2794 Cov.: 15 FAILED QC

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

GnomAD3 exomes AF: 0.177 AC: 29634 AN: 167744 Hom.: 13631 AF XY: 0.169 AC XY: 15315 AN XY: 90712

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 SAS exome AF: 0.0778

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

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.145

Gnomad4 ASJ exome AF: 0.322

Gnomad4 EAS exome AF: 0.290

Gnomad4 SAS exome AF: 0.130

Gnomad4 FIN exome AF: 0.327

Gnomad4 NFE exome AF: 0.152

Gnomad4 OTH exome AF: 0.210

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

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.0934

Gnomad4 ASJ AF: 0.227

Gnomad4 EAS AF: 0.193

Gnomad4 SAS AF: 0.0818

Gnomad4 FIN AF: 0.125

Gnomad4 NFE AF: 0.146

Gnomad4 OTH AF: 0.146

Alfa AF: 0.0691 Hom.: 139

ExAC AF: 0.215 AC: 22742

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs56066301; hg19: chr11-4976145; COSMIC: COSV66748088;