6-131700849-T-C

Position:

• chr6-131700849-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_030908.2(OR2A4):​c.553A>G​(p.Lys185Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 9)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: OR2A4 NM_030908.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.365

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]

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2114723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR2A4	NM_030908.2	c.553A>G	p.Lys185Glu	missense_variant	1/1	ENST00000315453.4	NP_112170.1
ENPP3	NM_005021.5	c.1412+7225T>C		intron_variant		ENST00000357639.8	NP_005012.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR2A4	ENST00000315453.4	c.553A>G	p.Lys185Glu	missense_variant	1/1	6	NM_030908.2	ENSP00000319546.2
ENPP3	ENST00000357639.8	c.1412+7225T>C		intron_variant		1	NM_005021.5	ENSP00000350265.3
ENPP3	ENST00000414305.5	c.1412+7225T>C		intron_variant		1		ENSP00000406261.1
ENPP3	ENST00000358229.6	c.1412+7225T>C		intron_variant		1		ENSP00000350964.5

Frequencies

GnomAD3 genomes Cov.: 9

GnomAD3 exomes AF: 0.00000981 AC: 2 AN: 203958 Hom.: 0 AF XY: 0.00000892 AC XY: 1 AN XY: 112126

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: 0.0000212

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000715 AC: 8 AN: 1118212 Hom.: 0 Cov.: 16 AF XY: 0.00000880 AC XY: 5 AN XY: 568348

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: 0.00000971

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 9

ExAC AF: 0.00000884 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

Jun 24, 2022

The c.553A>G (p.K185E) alteration is located in exon 1 (coding exon 1) of the OR2A4 gene. This alteration results from a A to G substitution at nucleotide position 553, causing the lysine (K) at amino acid position 185 to be replaced by a glutamic acid (E). 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	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.0070	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.00081	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.047
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.033	D
Polyphen		0.85	P
Vest4		0.11
MutPred		0.45		Loss of ubiquitination at K185 (P = 0.0309);
MVP		0.35
ClinPred		0.61	D
GERP RS		-3.6
Varity_R		0.40
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs749006568; hg19: chr6-132021989;