11-4923420-T-C

Position:

• chr11-4923420-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001005237.1(OR51G1):​c.920A>G​(p.Lys307Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000548 in 1,588,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (0 hom.)
• Consequence: OR51G1 NM_001005237.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.747

Genes affected

OR51G1 (HGNC:14738): (olfactory receptor family 51 subfamily G member 1) 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. This olfactory receptor gene is a segregating pseudogene, where some individuals have an allele that encodes a functional olfactory receptor, while other individuals have an allele encoding a protein that is predicted to be non-functional. [provided by RefSeq, Jun 2015]

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04285541).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR51G1	NM_001005237.1	c.920A>G	p.Lys307Arg	missense_variant	1/1	ENST00000623849.1	NP_001005237.1
MMP26	NM_021801.5	c.-144-64648T>C		intron_variant		ENST00000380390.6	NP_068573.2
MMP26	NM_001384608.1	c.-152-64850T>C		intron_variant			NP_001371537.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR51G1	ENST00000623849.1	c.920A>G	p.Lys307Arg	missense_variant	1/1	6	NM_001005237.1	ENSP00000485612.1
MMP26	ENST00000380390.6	c.-144-64648T>C		intron_variant		5	NM_021801.5	ENSP00000369753.1
MMP26	ENST00000300762.2	c.-152-64850T>C		intron_variant		1		ENSP00000300762.2

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000246 AC: 57 AN: 232120 Hom.: 0 AF XY: 0.000257 AC XY: 32 AN XY: 124572

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.0000311

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000494

Gnomad NFE exome AF: 0.000395

Gnomad OTH exome AF: 0.00143

GnomAD4 exome AF: 0.000576 AC: 828 AN: 1436274 Hom.: 0 Cov.: 30 AF XY: 0.000548 AC XY: 390 AN XY: 711440

Gnomad4 AFR exome AF: 0.0000918

Gnomad4 AMR exome AF: 0.0000237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000153

Gnomad4 NFE exome AF: 0.000722

Gnomad4 OTH exome AF: 0.000388

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74480

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000514

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000246

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000247 AC: 30

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

Nov 14, 2024

The c.920A>G (p.K307R) alteration is located in exon 1 (coding exon 1) of the OR51G1 gene. This alteration results from a A to G substitution at nucleotide position 920, causing the lysine (K) at amino acid position 307 to be replaced by an arginine (R). 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	0.061
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.00079	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.56	N
PrimateAI	Benign	0.30	T
Polyphen		0.59	P
ClinPred		0.019	T
GERP RS		4.2
Varity_R		0.073
gMVP		0.069

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs139588325; hg19: chr11-4944650;