chr6-131700503-A-G

Position:

chr6-131700503-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_030908.2(OR2A4):c.899T>C(p.Leu300Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000088 ( 1 hom., cov: 7)

Exomes 𝑓: 0.000014 ( 4 hom. )

Failed GnomAD Quality Control

Consequence

OR2A4
NM_030908.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.522

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 Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05891484).

BS2

High Homozygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR2A4	NM_030908.2 linkuse as main transcript	c.899T>C	p.Leu300Ser	missense_variant	1/1	ENST00000315453.4	NP_112170.1	O95047A0A126GVW2
ENPP3	NM_005021.5 linkuse as main transcript	c.1412+6879A>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.899T>C	p.Leu300Ser	missense_variant	1/1	6	NM_030908.2	ENSP00000319546.2	O95047
ENPP3	ENST00000357639.8 linkuse as main transcript	c.1412+6879A>G		intron_variant		1	NM_005021.5	ENSP00000350265.3	O14638
ENPP3	ENST00000414305.5 linkuse as main transcript	c.1412+6879A>G		intron_variant		1		ENSP00000406261.1	O14638
ENPP3	ENST00000358229.6 linkuse as main transcript	c.1412+6879A>G		intron_variant		1		ENSP00000350964.5	F8W6H5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

56468

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000737

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000752

AC:

AN:

212890

Hom.:

AF XY:

0.0000257

AC XY:

AN XY:

116716

show subpopulations

Gnomad AFR exome

AF:

0.00161

Gnomad AMR exome

AF:

0.0000365

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000141

AC:

AN:

1205822

Hom.:

Cov.:

AF XY:

0.00000822

AC XY:

AN XY:

608486

show subpopulations

Gnomad4 AFR exome

AF:

0.000628

Gnomad4 AMR exome

AF:

0.0000261

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:

0.000101

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000885

AC:

AN:

56512

Hom.:

Cov.:

AF XY:

0.0000377

AC XY:

AN XY:

26514

show subpopulations

Gnomad4 AFR

AF:

0.000736

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000485

Hom.:

ExAC

AF:

0.0000875

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

Dec 28, 2022

The c.899T>C (p.L300S) 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 899, causing the leucine (L) at amino acid position 300 to be replaced by a serine (S). 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

0.24

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.017

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.77

M_CAP

Benign

0.0029

MetaRNN

Benign

0.059

MetaSVM

Benign

-0.95

MutationAssessor

Pathogenic

3.2

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.087

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.36

MutPred

0.79

Gain of disorder (P = 0.0031);

MVP

0.51

ClinPred

0.18

GERP RS

0.069

Varity_R

0.59

gMVP

0.31

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