chr14-19748000-G-A

Position:

• chr14-19748000-G-A

Variant summary

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

The NM_001405963.1(OR4Q3):​c.597G>A​(p.Met199Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 36)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: OR4Q3 NM_001405963.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.32

Genes affected

OR4Q3 (HGNC:15426): (olfactory receptor family 4 subfamily Q member 3) 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]

OR4N2 (HGNC:14742): (olfactory receptor family 4 subfamily N 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 seven-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, Mar 2014]

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=0.03750372).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR4Q3	NM_001405963.1	c.597G>A	p.Met199Ile	missense_variant	2/2	ENST00000642117.2	NP_001392892.1
OR4Q3	NM_172194.1	c.573G>A	p.Met191Ile	missense_variant	1/1		NP_751944.1
OR4Q3	XM_024449618.1	c.762G>A	p.Met254Ile	missense_variant	3/4		XP_024305386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR4Q3	ENST00000642117.2	c.597G>A	p.Met199Ile	missense_variant	2/2		NM_001405963.1	ENSP00000492928	P1
OR4N2	ENST00000557414.1	c.-303-13888G>A		intron_variant				ENSP00000451462

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251030 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135662

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461700 Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9 AN XY: 727142

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 36

Alfa AF: 0.0000508 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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

Jan 24, 2024

The c.573G>A (p.M191I) alteration is located in exon 1 (coding exon 1) of the OR4Q3 gene. This alteration results from a G to A substitution at nucleotide position 573, causing the methionine (M) at amino acid position 191 to be replaced by an isoleucine (I). 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	0.20
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.90
DEOGEN2	Benign	0.0031	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.27	T;T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.038	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.15	.;N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.15	.;N
REVEL	Benign	0.020
Sift	Benign	0.074	.;T
Sift4G	Benign	0.11	.;T
Polyphen		0.0030	.;B
Vest4		0.12
MutPred		0.39		.;Loss of ubiquitination at K187 (P = 0.1453);
MVP		0.076
ClinPred		0.031	T
GERP RS		-1.4
Varity_R		0.15
gMVP		0.16

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-20216159;