chr15-22094529-T-G

Position:

• chr15-22094529-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001005241.4(OR4N4):​c.8T>G​(p.Ile3Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I3T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: OR4N4 NM_001005241.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.78

Genes affected

OR4N4 (HGNC:15375): (olfactory receptor family 4 subfamily N member 4) 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]

OR4M2-OT1 (HGNC:56199): (OR4M2 overlapping transcript 1)

OR4M2-OT1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0481762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR4N4	NM_001005241.4	c.8T>G	p.Ile3Arg	missense_variant	1/1	ENST00000328795.6	NP_001005241.2
OR4M2-OT1	NR_110480.1	n.840T>G		non_coding_transcript_exon_variant	8/9
OR4M2-OT1	NR_110481.1	n.572T>G		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR4N4	ENST00000328795.6	c.8T>G	p.Ile3Arg	missense_variant	1/1	6	NM_001005241.4	ENSP00000332500.4
OR4M2-OT1	ENST00000639059.1	c.8T>G	p.Ile3Arg	missense_variant	7/7	2		ENSP00000493899.1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.00000440 AC: 1 AN: 227524 Hom.: 0 AF XY: 0.00000818 AC XY: 1 AN XY: 122316

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000385

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

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

Aug 05, 2024

The c.8T>G (p.I3R) alteration is located in exon 1 (coding exon 1) of the OR4N4 gene. This alteration results from a T to G substitution at nucleotide position 8, causing the isoleucine (I) at amino acid position 3 to be replaced by an arginine (R). 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	0.061
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.013
DANN	Benign	0.45
DEOGEN2	Benign	0.0015	.;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.14	T;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-0.45	.;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.41	.;N
REVEL	Benign	0.036
Sift	Benign	0.53	.;T
Sift4G	Benign	0.54	.;T
Polyphen		0.0	.;B
Vest4		0.14
MutPred		0.35		Gain of solvent accessibility (P = 0.0063);Gain of solvent accessibility (P = 0.0063);
MVP		0.067
MPC		0.12
ClinPred		0.024	T
GERP RS		-6.7
Varity_R		0.038
gMVP		0.075

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs372302619; hg19: chr15-22382480;