11-4587363-T-C

Position:

• chr11-4587363-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001005170.4(OR52I2):​c.473T>C​(p.Ile158Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000658 in 1,459,064 control chromosomes in the GnomAD database, including 28 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00058 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000066 (28 hom.)
  • Failed GnomAD Quality Control
• Consequence: OR52I2 NM_001005170.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.41

Genes affected

OR52I2 (HGNC:15221): (olfactory receptor family 52 subfamily I 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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02016604).
• BP6: Variant 11-4587363-T-C is Benign according to our data. Variant chr11-4587363-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2345165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR52I2	NM_001005170.4	c.473T>C	p.Ile158Thr	missense_variant	1/1		NP_001005170.2
OR52I2	NM_001405760.1	c.473T>C	p.Ile158Thr	missense_variant	2/2		NP_001392689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR52I2	ENST00000641896.1	c.473T>C	p.Ile158Thr	missense_variant	2/2			ENSP00000493402.1
OR52I2	ENST00000641486.1	c.473T>C	p.Ile158Thr	missense_variant	1/1			ENSP00000493314.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 86 AN: 147410 Hom.: 1 Cov.: 33 FAILED QC

Gnomad AFR AF: 0.00198

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000331

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00147

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251158 Hom.: 2 AF XY: 0.0000589 AC XY: 8 AN XY: 135758

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000658 AC: 96 AN: 1459064 Hom.: 28 Cov.: 33 AF XY: 0.0000689 AC XY: 50 AN XY: 726016

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000583 AC: 86 AN: 147522 Hom.: 1 Cov.: 33 AF XY: 0.000568 AC XY: 41 AN XY: 72242

Gnomad4 AFR AF: 0.00197

Gnomad4 AMR AF: 0.000331

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00146

Alfa AF: 0.000671 Hom.: 2

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

OR52I2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.11
DANN	Benign	0.28
DEOGEN2	Benign	0.0024	.;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.14	.;T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.020	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.060	.;.;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.2	.;.;N
REVEL	Benign	0.017
Sift	Benign	0.41	.;.;T
Sift4G	Benign	0.25	.;.;T
Polyphen		0.0070	.;.;B
Vest4		0.040
MutPred		0.25		.;.;Loss of stability (P = 0.0657);
MVP		0.11
MPC		0.22
ClinPred		0.019	T
GERP RS		-0.48
Varity_R		0.047
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs779246501; hg19: chr11-4608593;