11-56136986-T-C

Variant names:

• chr11-56136986-T-C
• rs200617115
• NM_001004064.2:c.733A>G

Variant summary

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

The NM_001004064.2(OR8J3):​c.733A>G​(p.Met245Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,613,444 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: OR8J3 NM_001004064.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.15
• Publications: 2 publications found

Genes affected

OR8J3 (HGNC:15312): (olfactory receptor family 8 subfamily J member 3) Predicted to enable odorant binding activity and olfactory receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway and sensory perception of smell. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.043120533).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR8J3	NM_001004064.2	c.733A>G	p.Met245Val	missense_variant	Exon 2 of 2	ENST00000642058.1	NP_001004064.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR8J3	ENST00000642058.1	c.733A>G	p.Met245Val	missense_variant	Exon 2 of 2		NM_001004064.2	ENSP00000493166.1
OR8J3	ENST00000641913.1	c.733A>G	p.Met245Val	missense_variant	Exon 2 of 2			ENSP00000493417.1
OR8J3	ENST00000641489.1	n.82A>G		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000118

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000399 AC: 10 AN: 250466 AF XY: 0.0000148

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000127 AC: 185 AN: 1461226 Hom.: 0 Cov.: 33 AF XY: 0.000136 AC XY: 99 AN XY: 726910

African (AFR) AF: 0.0000299 AC: 1 AN: 33418

American (AMR) AF: 0.000202 AC: 9 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.000153 AC: 170 AN: 1111838

Other (OTH) AF: 0.0000497 AC: 3 AN: 60358

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74360

African (AFR) AF: 0.0000723 AC: 3 AN: 41466

American (AMR) AF: 0.000196 AC: 3 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.000144

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.733A>G (p.M245V) alteration is located in exon 1 (coding exon 1) of the OR8J3 gene. This alteration results from a A to G substitution at nucleotide position 733, causing the methionine (M) at amino acid position 245 to be replaced by a valine (V). 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	0.088
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	2.1
DANN	Benign	0.43
DEOGEN2	Benign	0.0049	T;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.67	.;.;T
M_CAP	Benign	0.00090	T
MetaRNN	Benign	0.043	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.79	N;N;N
PhyloP100		-1.2
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.8	.;.;N
REVEL	Benign	0.023
Sift	Uncertain	0.029	.;.;D
Sift4G	Uncertain	0.041	.;.;D
Polyphen		0.0030	B;B;B
Vest4		0.15
MVP		0.13
MPC		0.0097
ClinPred		0.035	T
GERP RS		-4.1
Varity_R		0.15
gMVP		0.26
Mutation Taster		=99/1	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: rs200617115; hg19: chr11-55904462; COSMIC: COSV56883296; COSMIC: COSV56883296;