Genetic Variant OR4A47:p.Leu25Ile (chr11-48488865-C-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001005512.2(OR4A47):c.73C>A(p.Leu25Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,612,516 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00080 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 4 hom. )

Consequence

OR4A47
NM_001005512.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.639

Variant links:

Genes affected

OR4A47 (HGNC:31266): (olfactory receptor family 4 subfamily A member 47) 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]

OR4A47 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR4A47	NM_001005512.2 link	c.73C>A	p.Leu25Ile	missense_variant	Exon 1 of 1	ENST00000446524.2	NP_001005512.2	Q6IF82

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR4A47	ENST00000446524.2 link	c.73C>A	p.Leu25Ile	missense_variant	Exon 1 of 1	6	NM_001005512.2	ENSP00000412752.1		Q6IF82

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000592

AC:

146

AN:

246746

Hom.:

AF XY:

0.000562

AC XY:

AN XY:

133468

show subpopulations

Gnomad AFR exome

AF:

0.000314

Gnomad AMR exome

AF:

0.0000587

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000140

Gnomad NFE exome

AF:

0.00120

Gnomad OTH exome

AF:

0.000500

GnomAD4 exome

AF:

0.00147

AC:

2147

AN:

1460376

Hom.:

Cov.:

AF XY:

0.00141

AC XY:

1026

AN XY:

726520

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000225

Gnomad4 NFE exome

AF:

0.00188

Gnomad4 OTH exome

AF:

0.000580

GnomAD4 genome

AF:

0.000802

AC:

122

AN:

152140

Hom.:

Cov.:

AF XY:

0.000673

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.000410

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00144

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.00109

Hom.:

Bravo

AF:

0.000824

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000602

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.73C>A (p.L25I) alteration is located in exon 1 (coding exon 1) of the OR4A47 gene. This alteration results from a C to A substitution at nucleotide position 73, causing the leucine (L) at amino acid position 25 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

0.11

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.75

DEOGEN2

Benign

0.0064

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.65

M_CAP

Benign

0.0048

MetaRNN

Benign

0.023

MetaSVM

Benign

-1.0

PrimateAI

Benign

0.23

PROVEAN

Benign

-1.4

REVEL

Benign

0.037

Sift

Benign

0.13

Sift4G

Benign

0.28

Polyphen

0.47

Vest4

0.097

MVP

0.040

ClinPred

0.019

GERP RS

-1.5

Varity_R

0.13

gMVP

0.072

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.32

Position offset: -4

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