chr1-248650079-T-G

Position:

• chr1-248650079-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001001824.2(OR2T27):​c.806A>C​(p.Glu269Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000317 in 1,572,998 control chromosomes in the GnomAD database, including 33 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. E269D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00035 (4 hom., cov: 26)
  • Exomes 𝑓: 0.00031 (29 hom.)
• Consequence: OR2T27 NM_001001824.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.108

Genes affected

OR2T27 (HGNC:31252): (olfactory receptor family 2 subfamily T member 27) 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004524976).
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR2T27	NM_001001824.2	c.806A>C	p.Glu269Ala	missense_variant	2/2	ENST00000460972.4
OR2T27	NM_001386060.1	c.806A>C	p.Glu269Ala	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR2T27	ENST00000460972.4	c.806A>C	p.Glu269Ala	missense_variant	2/2		NM_001001824.2	P1
OR2T27	ENST00000641652.1	c.806A>C	p.Glu269Ala	missense_variant	3/3			P1

Frequencies

GnomAD3 genomes AF: 0.000354 AC: 51 AN: 144182 Hom.: 4 Cov.: 26

Gnomad AFR AF: 0.0000260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000479

Gnomad ASJ AF: 0.00881

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000167

Gnomad OTH AF: 0.00100

GnomAD3 exomes AF: 0.000359 AC: 88 AN: 245432 Hom.: 5 AF XY: 0.000331 AC XY: 44 AN XY: 132778

Gnomad AFR exome AF: 0.0000643

Gnomad AMR exome AF: 0.000237

Gnomad ASJ exome AF: 0.00513

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.000832

GnomAD4 exome AF: 0.000313 AC: 447 AN: 1428816 Hom.: 29 Cov.: 33 AF XY: 0.000283 AC XY: 201 AN XY: 711362

Gnomad4 AFR exome AF: 0.0000312

Gnomad4 AMR exome AF: 0.000502

Gnomad4 ASJ exome AF: 0.00692

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.0000356

Gnomad4 FIN exome AF: 0.0000388

Gnomad4 NFE exome AF: 0.000177

Gnomad4 OTH exome AF: 0.000693

GnomAD4 genome AF: 0.000354 AC: 51 AN: 144182 Hom.: 4 Cov.: 26 AF XY: 0.000485 AC XY: 34 AN XY: 70032

Gnomad4 AFR AF: 0.0000260

Gnomad4 AMR AF: 0.000479

Gnomad4 ASJ AF: 0.00881

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000167

Gnomad4 OTH AF: 0.00100

Alfa AF: 0.00120 Hom.: 3

ExAC AF: 0.000450 AC: 54

EpiCase AF: 0.00

EpiControl AF: 0.000301

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The c.806A>C (p.E269A) alteration is located in exon 1 (coding exon 1) of the OR2T27 gene. This alteration results from a A to C substitution at nucleotide position 806, causing the glutamic acid (E) at amino acid position 269 to be replaced by an alanine (A). 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	0.099
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	15
DANN	Benign	0.62
DEOGEN2	Benign	0.0040	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.26	.;.;T
M_CAP	Benign	0.00094	T
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-3.1	.;.;D
REVEL	Benign	0.058
Sift	Benign	0.20	.;.;T
Sift4G	Benign	0.52	.;.;T
Polyphen		0.019	B;B;B
Vest4		0.10
MutPred		0.32		Loss of ubiquitination at K272 (P = 0.0496);Loss of ubiquitination at K272 (P = 0.0496);Loss of ubiquitination at K272 (P = 0.0496);
MVP		0.21
MPC		0.53
ClinPred		0.021	T
GERP RS		-0.86
Varity_R		0.15
gMVP		0.086

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs754424039; hg19: chr1-248813380;