rs200877558

Variant names:

• chr1-248273336-A-G
• rs200877558
• NM_001004695.2:c.479T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001004695.2(OR2T33):​c.479T>C​(p.Val160Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (17 hom., cov: 33)
  • Exomes 𝑓: 0.24 (66 hom.)
  • Failed GnomAD Quality Control
• Consequence: OR2T33 NM_001004695.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.73
• Publications: 12 publications found

Genes affected

OR2T33 (HGNC:31255): (olfactory receptor family 2 subfamily T member 33) 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024973452).
• BP6: Variant 1-248273336-A-G is Benign according to our data. Variant chr1-248273336-A-G is described in ClinVar as Benign. ClinVar VariationId is 403272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR2T33	NM_001004695.2	c.479T>C	p.Val160Ala	missense_variant	Exon 2 of 2	ENST00000641220.1	NP_001004695.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR2T33	ENST00000641220.1	c.479T>C	p.Val160Ala	missense_variant	Exon 2 of 2		NM_001004695.2	ENSP00000493437.1
OR2T33	ENST00000318021.4	c.479T>C	p.Val160Ala	missense_variant	Exon 1 of 1	6		ENSP00000324687.2

Frequencies

GnomAD3 genomes AF: 0.0386 AC: 4268 AN: 110592 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0554

Gnomad AMI AF: 0.0111

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0261

Gnomad EAS AF: 0.00915

Gnomad SAS AF: 0.0245

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.0340

Gnomad NFE AF: 0.0331

Gnomad OTH AF: 0.0414

GnomAD2 exomes AF: 0.281 AC: 46947 AN: 166848 AF XY: 0.289

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.269

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.118

Gnomad FIN exome AF: 0.395

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.259

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.244 AC: 211383 AN: 865754 Hom.: 66 Cov.: 121 AF XY: 0.235 AC XY: 101799 AN XY: 432548

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

African (AFR) AF: 0.166 AC: 3715 AN: 22352

American (AMR) AF: 0.168 AC: 4488 AN: 26732

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 2106 AN: 15804

East Asian (EAS) AF: 0.0289 AC: 932 AN: 32208

South Asian (SAS) AF: 0.0849 AC: 5009 AN: 59032

European-Finnish (FIN) AF: 0.159 AC: 5111 AN: 32216

Middle Eastern (MID) AF: 0.155 AC: 394 AN: 2548

European-Non Finnish (NFE) AF: 0.286 AC: 182615 AN: 637828

Other (OTH) AF: 0.189 AC: 7013 AN: 37034

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0387 AC: 4279 AN: 110664 Hom.: 17 Cov.: 33 AF XY: 0.0408 AC XY: 2202 AN XY: 53960

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

African (AFR) AF: 0.0555 AC: 1782 AN: 32114

American (AMR) AF: 0.0322 AC: 360 AN: 11166

Ashkenazi Jewish (ASJ) AF: 0.0261 AC: 63 AN: 2410

East Asian (EAS) AF: 0.00919 AC: 39 AN: 4244

South Asian (SAS) AF: 0.0248 AC: 95 AN: 3824

European-Finnish (FIN) AF: 0.0413 AC: 295 AN: 7150

Middle Eastern (MID) AF: 0.0368 AC: 7 AN: 190

European-Non Finnish (NFE) AF: 0.0331 AC: 1570 AN: 47384

Other (OTH) AF: 0.0410 AC: 60 AN: 1464

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.180 Hom.: 2

ExAC AF: 0.388 AC: 47132

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.35
DANN	Benign	0.22
DEOGEN2	Benign	0.0066	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0087	N
LIST_S2	Benign	0.0016	.;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.33	N;N
PhyloP100		-1.7
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.020	.;N
REVEL	Benign	0.017
Sift	Benign	1.0	.;T
Sift4G	Benign	0.48	.;T
Polyphen		0.0	B;B
Vest4		0.056
MPC		1.3
ClinPred		0.0030	T
GERP RS		-2.8
PromoterAI		-0.00030	Neutral
Varity_R		0.037
gMVP		0.13
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200877558; hg19: chr1-248436638; COSMIC: COSV58813722;