Genetic Variant NM_001005241.4:c.8T>C (chr15-22094529-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_001005241.4(OR4N4):c.8T>C(p.Ile3Thr) 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 0)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

OR4N4
NM_001005241.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.78

Variant links:

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]

OR4N4 links:

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

OR4M2-OT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029517293).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR4N4	NM_001005241.4 link	c.8T>C	p.Ile3Thr	missense_variant	Exon 1 of 1	ENST00000328795.6	NP_001005241.2	Q8N0Y3A0A126GVN2
OR4M2-OT1	NR_110480.1 link	n.840T>C		non_coding_transcript_exon_variant	Exon 8 of 9
OR4M2-OT1	NR_110481.1 link	n.572T>C		non_coding_transcript_exon_variant	Exon 6 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR4N4	ENST00000328795.6 link	c.8T>C	p.Ile3Thr	missense_variant	Exon 1 of 1	6	NM_001005241.4	ENSP00000332500.4		Q8N0Y3
OR4M2-OT1	ENST00000639059.1 link	c.8T>C	p.Ile3Thr	missense_variant	Exon 7 of 7	2		ENSP00000493899.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000703

AC:

AN:

227524

Hom.:

AF XY:

0.0000981

AC XY:

AN XY:

122316

show subpopulations

Gnomad AFR exome

AF:

0.0000632

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000725

Gnomad SAS exome

AF:

0.0000385

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000958

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

21758

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

11166

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000482

Hom.:

ExAC

AF:

0.0000332

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8T>C (p.I3T) alteration is located in exon 1 (coding exon 1) of the OR4N4 gene. This alteration results from a T to C substitution at nucleotide position 8, causing the isoleucine (I) at amino acid position 3 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

0.060

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.010

DANN

Benign

0.43

DEOGEN2

Benign

0.0015

.;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.17

T;.

M_CAP

Benign

0.0050

MetaRNN

Benign

0.030

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.20

.;N

PrimateAI

Benign

0.29

PROVEAN

Benign

0.79

.;N

REVEL

Benign

0.032

Sift

Benign

0.60

.;T

Sift4G

Benign

0.59

.;T

Polyphen

0.0

.;B

Vest4

0.044

MutPred

0.35

Gain of glycosylation at I3 (P = 0.0168);Gain of glycosylation at I3 (P = 0.0168);

MVP

0.055

MPC

0.086

ClinPred

0.011

GERP RS

-6.7

Varity_R

0.025

gMVP

0.034

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over