11-56094014-C-T

Variant names:

• chr11-56094014-C-T
• rs139437994
• NM_001003750.1:c.707C>T

Variant summary

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

The NM_001003750.1(OR8I2):​c.707C>T​(p.Ala236Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,613,882 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00028 (4 hom.)
• Consequence: OR8I2 NM_001003750.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98

Genes affected

OR8I2 (HGNC:15310): (olfactory receptor family 8 subfamily I member 2) 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=0.038435966).
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR8I2	NM_001003750.1	c.707C>T	p.Ala236Val	missense_variant	Exon 1 of 1	ENST00000302124.8	NP_001003750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR8I2	ENST00000302124.8	c.707C>T	p.Ala236Val	missense_variant	Exon 1 of 1	6	NM_001003750.1	ENSP00000303864.2

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000787

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.000379 AC: 95 AN: 250846 Hom.: 1 AF XY: 0.000339 AC XY: 46 AN XY: 135556

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000432

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000276 AC: 403 AN: 1461658 Hom.: 4 Cov.: 34 AF XY: 0.000274 AC XY: 199 AN XY: 727126

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000196

Gnomad4 OTH exome AF: 0.000679

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152224 Hom.: 0 Cov.: 31 AF XY: 0.000645 AC XY: 48 AN XY: 74422

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.000786

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000449 Hom.: 1

Bravo AF: 0.000680

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000830

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 21, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.707C>T (p.A236V) alteration is located in exon 1 (coding exon 1) of the OR8I2 gene. This alteration results from a C to T substitution at nucleotide position 707, causing the alanine (A) at amino acid position 236 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	0.14
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0067	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.11
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.035	D
Polyphen		0.90	P
Vest4		0.17
MVP		0.46
MPC		0.010
ClinPred		0.044	T
GERP RS		3.4
Varity_R		0.30
gMVP		0.13

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: rs139437994; hg19: chr11-55861490;