6-131701316-A-G

Position:

chr6-131701316-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030908.2(OR2A4):c.86T>C(p.Leu29Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000255 in 1,609,948 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000067 ( 0 hom., cov: 21)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

OR2A4
NM_030908.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.63

Variant links:

Genes affected

OR2A4 (HGNC:14729): (olfactory receptor family 2 subfamily A 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]

OR2A4 links:

ENPP3 (HGNC:3358): (ectonucleotide pyrophosphatase/phosphodiesterase 3) The protein encoded by this gene belongs to a series of ectoenzymes that are involved in hydrolysis of extracellular nucleotides. These ectoenzymes possess ATPase and ATP pyrophosphatase activities and are type II transmembrane proteins. Expression of the related rat mRNA has been found in a subset of immature glial cells and in the alimentary tract. The corresponding rat protein has been detected in the pancreas, small intestine, colon, and liver. The human mRNA is expressed in glioma cells, prostate, and uterus. Expression of the human protein has been detected in uterus, basophils, and mast cells. Two transcript variants, one protein coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Oct 2015]

ENPP3 links:

ENPP3 (HGNC:):

ENPP3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR2A4	NM_030908.2 linkuse as main transcript	c.86T>C	p.Leu29Pro	missense_variant	1/1	ENST00000315453.4	NP_112170.1	O95047A0A126GVW2
ENPP3	NM_005021.5 linkuse as main transcript	c.1412+7692A>G		intron_variant		ENST00000357639.8	NP_005012.2	O14638

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
OR2A4	ENST00000315453.4 linkuse as main transcript	c.86T>C	p.Leu29Pro	missense_variant	1/1	6	NM_030908.2	ENSP00000319546.2	O95047
ENPP3	ENST00000357639.8 linkuse as main transcript	c.1412+7692A>G		intron_variant		1	NM_005021.5	ENSP00000350265.3	O14638
ENPP3	ENST00000414305.5 linkuse as main transcript	c.1412+7692A>G		intron_variant		1		ENSP00000406261.1	O14638
ENPP3	ENST00000358229.6 linkuse as main transcript	c.1412+7692A>G		intron_variant		1		ENSP00000350964.5	F8W6H5

Frequencies

GnomAD3 genomes

AF:

0.0000666

AC:

AN:

150142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000492

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000466

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000242

AC:

AN:

248050

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000868

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:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1459806

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

726386

show subpopulations

Gnomad4 AFR exome

AF:

0.0000898

Gnomad4 AMR exome

AF:

0.000112

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:

0.0000171

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000666

AC:

AN:

150142

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73148

show subpopulations

Gnomad4 AFR

AF:

0.0000492

Gnomad4 AMR

AF:

0.000466

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000128

ExAC

AF:

0.00000831

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.86T>C (p.L29P) alteration is located in exon 1 (coding exon 1) of the OR2A4 gene. This alteration results from a T to C substitution at nucleotide position 86, causing the leucine (L) at amino acid position 29 to be replaced by a proline (P). 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

0.16

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.093

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.066

LIST_S2

Benign

0.48

M_CAP

Benign

0.0053

MetaRNN

Uncertain

0.53

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.21

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.98

Vest4

0.42

MutPred

0.76

Loss of stability (P = 0.0162);

MVP

0.53

ClinPred

0.95

GERP RS

1.4

Varity_R

0.77

gMVP

0.61

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

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