6-131700861-A-C

Position:

• chr6-131700861-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_030908.2(OR2A4):​c.541T>G​(p.Leu181Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., cov: 9)
  • Exomes 𝑓: 0.0036 (122 hom.)
  • Failed GnomAD Quality Control
• Consequence: OR2A4 NM_030908.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.16

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004045248).
• BP6: Variant 6-131700861-A-C is Benign according to our data. Variant chr6-131700861-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3205007.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR2A4	NM_030908.2	c.541T>G	p.Leu181Val	missense_variant	1/1	ENST00000315453.4	NP_112170.1
ENPP3	NM_005021.5	c.1412+7237A>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.541T>G	p.Leu181Val	missense_variant	1/1	6	NM_030908.2	ENSP00000319546.2
ENPP3	ENST00000357639.8	c.1412+7237A>C		intron_variant		1	NM_005021.5	ENSP00000350265.3
ENPP3	ENST00000414305.5	c.1412+7237A>C		intron_variant		1		ENSP00000406261.1
ENPP3	ENST00000358229.6	c.1412+7237A>C		intron_variant		1		ENSP00000350964.5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 41 AN: 67530 Hom.: 0 Cov.: 9 FAILED QC

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00617

Gnomad AMR AF: 0.000390

Gnomad ASJ AF: 0.000481

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00142

Gnomad FIN AF: 0.000192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000357

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00627 AC: 1185 AN: 189132 Hom.: 54 AF XY: 0.00588 AC XY: 611 AN XY: 103986

Gnomad AFR exome AF: 0.0690

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.000611

Gnomad EAS exome AF: 0.000148

Gnomad SAS exome AF: 0.00607

Gnomad FIN exome AF: 0.000153

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00505

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00358 AC: 3768 AN: 1052864 Hom.: 122 Cov.: 14 AF XY: 0.00351 AC XY: 1886 AN XY: 536572

Gnomad4 AFR exome AF: 0.0452

Gnomad4 AMR exome AF: 0.00480

Gnomad4 ASJ exome AF: 0.00140

Gnomad4 EAS exome AF: 0.000117

Gnomad4 SAS exome AF: 0.00629

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.00251

Gnomad4 OTH exome AF: 0.00602

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000607 AC: 41 AN: 67578 Hom.: 0 Cov.: 9 AF XY: 0.000699 AC XY: 22 AN XY: 31456

Gnomad4 AFR AF: 0.00199

Gnomad4 AMR AF: 0.000388

Gnomad4 ASJ AF: 0.000481

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00142

Gnomad4 FIN AF: 0.000192

Gnomad4 NFE AF: 0.000357

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00933 Hom.: 0

ExAC AF: 0.0000898 AC: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	12
DANN	Benign	0.78
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.00080	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.010
Sift	Benign	0.34	T
Sift4G	Benign	1.0	T
Polyphen		0.020	B
Vest4		0.059
MVP		0.22
ClinPred		0.0071	T
GERP RS		-3.6
Varity_R		0.14
gMVP		0.044

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

Other links and lift over

dbSNP: rs62622403; hg19: chr6-132022001;