11-124265677-C-T

Variant names:

• chr11-124265677-C-T
• rs992029489
• NM_001005198.2:c.746C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001005198.2(OR8G5):​c.746C>T​(p.Ser249Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: OR8G5 NM_001005198.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.32

Genes affected

OR8G5 (HGNC:19622): (olfactory receptor family 8 subfamily G member 5) 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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15649989).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR8G5	NM_001005198.2	c.746C>T	p.Ser249Phe	missense_variant	Exon 2 of 2	ENST00000641992.2	NP_001005198.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR8G5	ENST00000641992.2	c.746C>T	p.Ser249Phe	missense_variant	Exon 2 of 2		NM_001005198.2	ENSP00000493127.1
OR8G5	ENST00000641707.1	c.746C>T	p.Ser249Phe	missense_variant	Exon 1 of 1			ENSP00000493069.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461738 Hom.: 0 Cov.: 36 AF XY: 0.00000550 AC XY: 4 AN XY: 727150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.851C>T (p.S284F) alteration is located in exon 1 (coding exon 1) of the OR8G5 gene. This alteration results from a C to T substitution at nucleotide position 851, causing the serine (S) at amino acid position 284 to be replaced by a phenylalanine (F). 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	0.12
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	15
DANN	Benign	0.87
DEOGEN2	Benign	0.015	.;.;T
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.40	.;T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.16	T;T;T
MutationAssessor	Benign	1.6	.;.;L
Sift4G	Benign	0.063	.;.;T
Vest4		0.16
MVP		0.093
MPC		0.18
GERP RS		2.3
Varity_R		0.18
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs992029489; hg19: chr11-124135573; COSMIC: COSV100422388;