11-4594213-C-T

Variant names:

• chr11-4594213-C-T
• rs200284101
• NM_001005169.1:c.175C>T

Variant summary

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

The NM_001005169.1(OR52I1):​c.175C>T​(p.Arg59Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,614,038 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: OR52I1 NM_001005169.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47

Genes affected

OR52I1 (HGNC:15220): (olfactory receptor family 52 subfamily I 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. [provided by RefSeq, Jul 2008]

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=0.01755476).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR52I1	NM_001005169.1	c.175C>T	p.Arg59Trp	missense_variant	Exon 1 of 1	ENST00000530443.4	NP_001005169.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR52I1	ENST00000530443.4	c.175C>T	p.Arg59Trp	missense_variant	Exon 1 of 1	6	NM_001005169.1	ENSP00000436453.1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152076 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000366 AC: 92 AN: 251298 Hom.: 1 AF XY: 0.000339 AC XY: 46 AN XY: 135816

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000252 AC: 368 AN: 1461846 Hom.: 1 Cov.: 56 AF XY: 0.000248 AC XY: 180 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00547

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000150

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152192 Hom.: 0 Cov.: 31 AF XY: 0.000470 AC XY: 35 AN XY: 74414

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00236

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000653 Hom.: 0

Bravo AF: 0.000423

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000280 AC: 34

EpiCase AF: 0.000218

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.175C>T (p.R59W) alteration is located in exon 1 (coding exon 1) of the OR52I1 gene. This alteration results from a C to T substitution at nucleotide position 175, causing the arginine (R) at amino acid position 59 to be replaced by a tryptophan (W). 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	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0089	T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.10	N;.
REVEL	Benign	0.084
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.39	B;.
Vest4		0.23
MVP		0.44
MPC		0.42
ClinPred		0.11	T
GERP RS		3.7
Varity_R		0.20
gMVP		0.38

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: rs200284101; hg19: chr11-4615443;