chr11-4955504-C-A

Variant names:

• chr11-4955504-C-A
• rs753764563
• NM_001004748.1:c.210G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001004748.1(OR51A2):​c.210G>T​(p.Met70Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000091 (0 hom., cov: 17)
  • Exomes 𝑓: 0.000082 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OR51A2 NM_001004748.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.22
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028194845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR51A2	NM_001004748.1	c.210G>T	p.Met70Ile	missense_variant	Exon 1 of 1	ENST00000380371.1	NP_001004748.1
MMP26	NM_021801.5	c.-144-32564C>A		intron_variant	Intron 2 of 7	ENST00000380390.6	NP_068573.2
MMP26	NM_001384608.1	c.-152-32766C>A		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.210G>T	p.Met70Ile	missense_variant	Exon 1 of 1	6	NM_001004748.1	ENSP00000369729.1
MMP26	ENST00000380390.6	c.-144-32564C>A		intron_variant	Intron 2 of 7	5	NM_021801.5	ENSP00000369753.1
MMP26	ENST00000300762.2	c.-152-32766C>A		intron_variant	Intron 2 of 7	1		ENSP00000300762.2

Frequencies

GnomAD3 genomes AF: 0.0000911 AC: 11 AN: 120756 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.0000288

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000178

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: 0.000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000905 AC: 19 AN: 209870 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000382

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000653

Gnomad OTH exome AF: 0.000388

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000825 AC: 98 AN: 1188394 Hom.: 0 Cov.: 31 AF XY: 0.0000704 AC XY: 42 AN XY: 596750

African (AFR) AF: 0.0000674 AC: 2 AN: 29666

American (AMR) AF: 0.000370 AC: 14 AN: 37790

Ashkenazi Jewish (ASJ) AF: 0.0000441 AC: 1 AN: 22692

East Asian (EAS) AF: 0.00 AC: 0 AN: 36848

South Asian (SAS) AF: 0.00 AC: 0 AN: 80790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4654

European-Non Finnish (NFE) AF: 0.0000891 AC: 78 AN: 875126

Other (OTH) AF: 0.0000583 AC: 3 AN: 51494

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000910 AC: 11 AN: 120874 Hom.: 0 Cov.: 17 AF XY: 0.0000854 AC XY: 5 AN XY: 58552

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

African (AFR) AF: 0.0000287 AC: 1 AN: 34850

American (AMR) AF: 0.000178 AC: 2 AN: 11262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2750

East Asian (EAS) AF: 0.00 AC: 0 AN: 3838

South Asian (SAS) AF: 0.00 AC: 0 AN: 3996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.000148 AC: 8 AN: 53884

Other (OTH) AF: 0.00 AC: 0 AN: 1594

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000241 Hom.: 0

ExAC AF: 0.000111 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.210G>T (p.M70I) alteration is located in exon 1 (coding exon 1) of the OR51A2 gene. This alteration results from a G to T substitution at nucleotide position 210, causing the methionine (M) at amino acid position 70 to be replaced by an isoleucine (I). 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	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.0020
DANN	Benign	0.63
DEOGEN2	Benign	0.00036	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0045	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.5	N
PhyloP100		-5.2
PROVEAN	Benign	0.41	N
REVEL	Benign	0.010
Sift	Benign	0.27	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.026
MutPred		0.24		Loss of disorder (P = 0.0786);
MVP		0.27
MPC		1.2
ClinPred		0.034	T
GERP RS		-5.4
PromoterAI		-0.011	Neutral
Varity_R		0.059
gMVP		0.13
Mutation Taster		=99/1	polymorphism

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: rs753764563; hg19: chr11-4976734;