chr1-248650067-G-C

Variant names:

• chr1-248650067-G-C
• rs750254363
• NM_001001824.2:c.818C>G

Variant summary

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

The NM_001001824.2(OR2T27):​c.818C>G​(p.Ala273Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000321 in 1,572,536 control chromosomes in the GnomAD database, including 36 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 (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (4 hom., cov: 26)
  • Exomes 𝑓: 0.00032 (32 hom.)
• Consequence: OR2T27 NM_001001824.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.315

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=0.011996597).
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR2T27	NM_001001824.2	c.818C>G	p.Ala273Gly	missense_variant	Exon 2 of 2	ENST00000460972.4	NP_001001824.1
OR2T27	NM_001386060.1	c.818C>G	p.Ala273Gly	missense_variant	Exon 3 of 3		NP_001372989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR2T27	ENST00000460972.4	c.818C>G	p.Ala273Gly	missense_variant	Exon 2 of 2	6	NM_001001824.2	ENSP00000493412.1
OR2T27	ENST00000641652.1	c.818C>G	p.Ala273Gly	missense_variant	Exon 3 of 3			ENSP00000493434.1

Frequencies

GnomAD3 genomes AF: 0.000360 AC: 52 AN: 144536 Hom.: 4 Cov.: 26

Gnomad AFR AF: 0.0000520

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000478

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: 0.000998

GnomAD3 exomes AF: 0.000346 AC: 85 AN: 245642 Hom.: 5 AF XY: 0.000331 AC XY: 44 AN XY: 132884

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000236

Gnomad ASJ exome AF: 0.00502

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.000831

GnomAD4 exome AF: 0.000317 AC: 452 AN: 1428000 Hom.: 32 Cov.: 33 AF XY: 0.000287 AC XY: 204 AN XY: 710966

Gnomad4 AFR exome AF: 0.0000315

Gnomad4 AMR exome AF: 0.000525

Gnomad4 ASJ exome AF: 0.00711

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.0000356

Gnomad4 FIN exome AF: 0.0000388

Gnomad4 NFE exome AF: 0.000175

Gnomad4 OTH exome AF: 0.000710

GnomAD4 genome AF: 0.000360 AC: 52 AN: 144536 Hom.: 4 Cov.: 26 AF XY: 0.000498 AC XY: 35 AN XY: 70226

Gnomad4 AFR AF: 0.0000520

Gnomad4 AMR AF: 0.000478

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: 0.000998

Alfa AF: 0.00120 Hom.: 3

ExAC AF: 0.000450 AC: 54

EpiCase AF: 0.00

EpiControl AF: 0.000300

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.818C>G (p.A273G) alteration is located in exon 1 (coding exon 1) of the OR2T27 gene. This alteration results from a C to G substitution at nucleotide position 818, causing the alanine (A) at amino acid position 273 to be replaced by a glycine (G). 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	0.13
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.010	T;T;T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.17	.;.;T
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.92	T
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-2.8	.;.;D
REVEL	Benign	0.057
Sift	Pathogenic	0.0	.;.;D
Sift4G	Uncertain	0.038	.;.;D
Polyphen		0.85	P;P;P
Vest4		0.29
MutPred		0.52		Gain of ubiquitination at K272 (P = 0.0913);Gain of ubiquitination at K272 (P = 0.0913);Gain of ubiquitination at K272 (P = 0.0913);
MVP		0.33
MPC		0.92
ClinPred		0.10	T
GERP RS		-0.78
Varity_R		0.51
gMVP		0.029

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs750254363; hg19: chr1-248813368;