9-104604789-A-G

Position:

• chr9-104604789-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001004481.1(OR13C2):​c.839T>C​(p.Ile280Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,613,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I280R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: OR13C2 NM_001004481.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.884

Genes affected

OR13C2 (HGNC:14701): (olfactory receptor family 13 subfamily C 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]

LOC107987105 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052564055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR13C2	NM_001004481.1	c.839T>C	p.Ile280Thr	missense_variant	1/1	ENST00000542196.2
LOC107987105	XR_007061705.1	n.427+17241T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR13C2	ENST00000542196.2	c.839T>C	p.Ile280Thr	missense_variant	1/1		NM_001004481.1	P1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151698 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000731

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000191 AC: 48 AN: 251136 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135724

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1461650 Hom.: 0 Cov.: 34 AF XY: 0.000110 AC XY: 80 AN XY: 727138

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.000537

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000666

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151814 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74244

Gnomad4 AFR AF: 0.0000729

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000306 Hom.: 0

Bravo AF: 0.000230

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000124 AC: 15

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.839T>C (p.I280T) alteration is located in exon 1 (coding exon 1) of the OR13C2 gene. This alteration results from a T to C substitution at nucleotide position 839, causing the isoleucine (I) at amino acid position 280 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	0.24
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.17
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.044	D
Polyphen		0.34	B
Vest4		0.52
MVP		0.37
MPC		0.62
ClinPred		0.045	T
GERP RS		2.3
Varity_R		0.15
gMVP		0.059

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: rs144747138; hg19: chr9-107367070;