chr11-4587365-G-T

Position:

• chr11-4587365-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001005170.4(OR52I2):​c.475G>T​(p.Ala159Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000562 in 1,458,126 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00068 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (33 hom.)
  • Failed GnomAD Quality Control
• Consequence: OR52I2 NM_001005170.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -4.84

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015146345).
• BP6: Variant 11-4587365-G-T is Benign according to our data. Variant chr11-4587365-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2344611.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR52I2	NM_001005170.4	c.475G>T	p.Ala159Ser	missense_variant	1/1		NP_001005170.2
OR52I2	NM_001405760.1	c.475G>T	p.Ala159Ser	missense_variant	2/2		NP_001392689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR52I2	ENST00000641896.1	c.475G>T	p.Ala159Ser	missense_variant	2/2			ENSP00000493402.1
OR52I2	ENST00000641486.1	c.475G>T	p.Ala159Ser	missense_variant	1/1			ENSP00000493314.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 100 AN: 147130 Hom.: 1 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.00245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000332

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00148

GnomAD3 exomes AF: 0.0000717 AC: 18 AN: 251166 Hom.: 9 AF XY: 0.0000884 AC XY: 12 AN XY: 135764

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000562 AC: 82 AN: 1458126 Hom.: 33 Cov.: 33 AF XY: 0.0000537 AC XY: 39 AN XY: 725602

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000679 AC: 100 AN: 147240 Hom.: 1 Cov.: 32 AF XY: 0.000693 AC XY: 50 AN XY: 72136

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.000331

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00146

Alfa AF: 0.000432 Hom.: 2

ExAC AF: 0.000107 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.553G>T (p.A185S) alteration is located in exon 1 (coding exon 1) of the OR52I2 gene. This alteration results from a G to T substitution at nucleotide position 553, causing the alanine (A) at amino acid position 185 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.055
DANN	Benign	0.60
DEOGEN2	Benign	0.0013	.;.;T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.29	.;T;T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.015	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.18	.;.;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.66	.;.;N
REVEL	Benign	0.083
Sift	Benign	0.16	.;.;T
Sift4G	Uncertain	0.060	.;.;T
Polyphen		0.027	.;.;B
Vest4		0.021
MutPred		0.34		.;.;Gain of glycosylation at A185 (P = 0.0298);
MVP		0.41
MPC		0.16
ClinPred		0.033	T
GERP RS		-8.4
Varity_R		0.058
gMVP		0.12

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: rs753062989; hg19: chr11-4608595;