1-247921294-G-A

Variant names:

• chr1-247921294-G-A
• rs746072977
• NM_001005522.2:c.277G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001005522.2(OR2T8):​c.277G>A​(p.Ala93Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000017 (0 hom., cov: 15)
  • Exomes 𝑓: 0.000011 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OR2T8 NM_001005522.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.17
• Publications: 1 publications found

Genes affected

OR2T8 (HGNC:15020): (olfactory receptor family 2 subfamily T member 8) 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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05742684).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR2T8	NM_001005522.2	c.277G>A	p.Ala93Thr	missense_variant	Exon 2 of 2	ENST00000641945.2	NP_001005522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR2T8	ENST00000641945.2	c.277G>A	p.Ala93Thr	missense_variant	Exon 2 of 2		NM_001005522.2	ENSP00000493286.1

Frequencies

GnomAD3 genomes AF: 0.0000174 AC: 2 AN: 115106 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000176

Gnomad OTH AF: 0.000690

GnomAD2 exomes AF: 0.0000233 AC: 3 AN: 128654 AF XY: 0.0000301

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000111 AC: 11 AN: 987966 Hom.: 0 Cov.: 16 AF XY: 0.0000120 AC XY: 6 AN XY: 500530

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24028

American (AMR) AF: 0.00 AC: 0 AN: 32558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19558

East Asian (EAS) AF: 0.00 AC: 0 AN: 34190

South Asian (SAS) AF: 0.00 AC: 0 AN: 63670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3120

European-Non Finnish (NFE) AF: 0.0000153 AC: 11 AN: 718672

Other (OTH) AF: 0.00 AC: 0 AN: 44124

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000174 AC: 2 AN: 115106 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 53686

African (AFR) AF: 0.00 AC: 0 AN: 28380

American (AMR) AF: 0.00 AC: 0 AN: 10232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3038

East Asian (EAS) AF: 0.00 AC: 0 AN: 4132

South Asian (SAS) AF: 0.00 AC: 0 AN: 2824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000176 AC: 1 AN: 56868

Other (OTH) AF: 0.000690 AC: 1 AN: 1450

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000195 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.277G>A (p.A93T) alteration is located in exon 1 (coding exon 1) of the OR2T8 gene. This alteration results from a G to A substitution at nucleotide position 277, causing the alanine (A) at amino acid position 93 to be replaced by a threonine (T). 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	0.086
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.0
DANN	Benign	0.84
DEOGEN2	Benign	0.0061	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.55	.;T
M_CAP	Benign	0.00081	T
MetaRNN	Benign	0.057	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.86	L;L
PhyloP100		-4.2
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.5	.;N
REVEL	Benign	0.041
Sift	Benign	0.21	.;T
Sift4G	Benign	0.34	.;T
Polyphen		0.67	P;P
Vest4		0.066
MVP		0.25
ClinPred		0.094	T
GERP RS		-7.6
Varity_R		0.059
gMVP		0.026
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs746072977; hg19: chr1-248084596;