Genetic Variant OR2T11:p.Met133Lys (chr1-248626731-A-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001001964.2(OR2T11):c.398T>A(p.Met133Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000149 in 1,573,416 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a pathogenic 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. M133I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 3 hom., cov: 28)

Exomes 𝑓: 0.00015 ( 21 hom. )

Consequence

OR2T11
NM_001001964.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.14

Variant links:

Genes affected

OR2T11 (HGNC:19574): (olfactory receptor family 2 subfamily T member 11) 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]

OR2T11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.785

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR2T11	NM_001001964.2 link	c.398T>A	p.Met133Lys	missense_variant	Exon 2 of 2	ENST00000641193.1	NP_001001964.1	Q8NH01

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR2T11	ENST00000641193.1 link	c.398T>A	p.Met133Lys	missense_variant	Exon 2 of 2		NM_001001964.2	ENSP00000492951.1		Q8NH01

Frequencies

GnomAD3 genomes

AF:

0.000133

AC:

AN:

142802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000273

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:

0.000121

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000123

AC:

AN:

244566

Hom.:

AF XY:

0.0000982

AC XY:

AN XY:

132404

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000889

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:

0.000225

Gnomad OTH exome

AF:

0.000333

GnomAD4 exome

AF:

0.000150

AC:

215

AN:

1430614

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

711892

show subpopulations

Gnomad4 AFR exome

AF:

0.0000651

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000582

Gnomad4 NFE exome

AF:

0.000182

Gnomad4 OTH exome

AF:

0.000101

GnomAD4 genome

AF:

0.000133

AC:

AN:

142802

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

AN XY:

69580

show subpopulations

Gnomad4 AFR

AF:

0.000194

Gnomad4 AMR

AF:

0.000273

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000121

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000182

Hom.:

ExAC

AF:

0.0000926

AC:

EpiCase

AF:

0.000277

EpiControl

AF:

0.0000603

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.398T>A (p.M133K) alteration is located in exon 1 (coding exon 1) of the OR2T11 gene. This alteration results from a T to A substitution at nucleotide position 398, causing the methionine (M) at amino acid position 133 to be replaced by a lysine (K). 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

0.24

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0091

T;T

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

.;D

M_CAP

Benign

0.0070

MetaRNN

Pathogenic

0.79

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

4.2

H;H

PrimateAI

Uncertain

0.55

Polyphen

0.99

D;D

ClinPred

0.80

GERP RS

4.4

Varity_R

0.94

gMVP

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over