chr15-22095087-G-T

Position:

• chr15-22095087-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_001005241.4(OR4N4):​c.566G>T​(p.Cys189Phe) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 9)
• Consequence: OR4N4 NM_001005241.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.43

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR4N4	NM_001005241.4	c.566G>T	p.Cys189Phe	missense_variant	1/1	ENST00000328795.6
OR4M2-OT1	NR_110480.1	n.1103-264G>T		intron_variant, non_coding_transcript_variant
OR4M2-OT1	NR_110481.1	n.835-264G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR4N4	ENST00000328795.6	c.566G>T	p.Cys189Phe	missense_variant	1/1		NM_001005241.4	P1

Frequencies

GnomAD3 genomes Cov.: 9

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 248968 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134484

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 9

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

Feb 28, 2024

The c.566G>T (p.C189F) alteration is located in exon 1 (coding exon 1) of the OR4N4 gene. This alteration results from a G to T substitution at nucleotide position 566, causing the cysteine (C) at amino acid position 189 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	0.22
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;.
M_CAP	Benign	0.0039	T
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	4.1	.;H
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-11	.;D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	.;D
Vest4		0.76
MutPred		0.58		Loss of methylation at K186 (P = 0.1171);Loss of methylation at K186 (P = 0.1171);
MVP		0.84
MPC		0.51
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.97
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs1446792949; hg19: chr15-22383038;