rs12577167

Positions:

• chr11-5453888-A-G
• chr11-5453888-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001004754.3(OR51I2):​c.400A>G​(p.Thr134Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,613,978 control chromosomes in the GnomAD database, including 18,745 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.13 (1598 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17147 hom.)
• Consequence: OR51I2 NM_001004754.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38

Genes affected

OR51I2 (HGNC:15201): (olfactory receptor family 51 subfamily I member 2) 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]

HBE1 (HGNC:4830): (hemoglobin subunit epsilon 1) The epsilon globin gene (HBE) is normally expressed in the embryonic yolk sac: two epsilon chains together with two zeta chains (an alpha-like globin) constitute the embryonic hemoglobin Hb Gower I; two epsilon chains together with two alpha chains form the embryonic Hb Gower II. Both of these embryonic hemoglobins are normally supplanted by fetal, and later, adult hemoglobin. The five beta-like globin genes are found within a 45 kb cluster on chromosome 11 in the following order: 5'-epsilon - G-gamma - A-gamma - delta - beta-3' [provided by RefSeq, Jul 2008]

ENSG00000239920 (HGNC:):

OR51B5 (HGNC:19599): (olfactory receptor family 51 subfamily B member 5) 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]

HBG2 (HGNC:4832): (hemoglobin subunit gamma 2) The gamma globin genes (HBG1 and HBG2) are normally expressed in the fetal liver, spleen and bone marrow. Two gamma chains together with two alpha chains constitute fetal hemoglobin (HbF) which is normally replaced by adult hemoglobin (HbA) at birth. In some beta-thalassemias and related conditions, gamma chain production continues into adulthood. The two types of gamma chains differ at residue 136 where glycine is found in the G-gamma product (HBG2) and alanine is found in the A-gamma product (HBG1). The former is predominant at birth. The order of the genes in the beta-globin cluster is: 5'- epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001234293).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR51I2	NM_001004754.3	c.400A>G	p.Thr134Ala	missense_variant	2/2	ENST00000641930.1	NP_001004754.1
OR51B5	NM_001005567.3	c.-360+51681T>C		intron_variant			NP_001005567.2
OR51B5	NR_038321.2	n.84+51681T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR51I2	ENST00000641930.1	c.400A>G	p.Thr134Ala	missense_variant	2/2		NM_001004754.3	ENSP00000493016.1
ENSG00000239920	ENST00000380259.7	n.*740-107989T>C		intron_variant		5		ENSP00000369609.3

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20088 AN: 151998 Hom.: 1591 Cov.: 32

Gnomad AFR AF: 0.0798

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.151

GnomAD3 exomes AF: 0.168 AC: 42145 AN: 251436 Hom.: 4426 AF XY: 0.173 AC XY: 23502 AN XY: 135888

Gnomad AFR exome AF: 0.0767

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.111

Gnomad EAS exome AF: 0.371

Gnomad SAS exome AF: 0.270

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.142 AC: 207852 AN: 1461862 Hom.: 17147 Cov.: 60 AF XY: 0.147 AC XY: 106567 AN XY: 727236

Gnomad4 AFR exome AF: 0.0799

Gnomad4 AMR exome AF: 0.176

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.339

Gnomad4 SAS exome AF: 0.266

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.132 AC: 20107 AN: 152116 Hom.: 1598 Cov.: 32 AF XY: 0.137 AC XY: 10188 AN XY: 74376

Gnomad4 AFR AF: 0.0798

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.366

Gnomad4 SAS AF: 0.282

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.129

Gnomad4 OTH AF: 0.160

Alfa AF: 0.138 Hom.: 4046

Bravo AF: 0.131

TwinsUK AF: 0.127 AC: 472

ALSPAC AF: 0.138 AC: 531

ESP6500AA AF: 0.0697 AC: 307

ESP6500EA AF: 0.127 AC: 1091

ExAC AF: 0.166 AC: 20194

Asia WGS AF: 0.292 AC: 1014 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.141

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.7
DANN	Benign	0.95
DEOGEN2	Benign	0.014	T;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.64	.;T
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.30	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.5	.;N
REVEL	Benign	0.078
Sift	Benign	0.27	.;T
Sift4G	Benign	0.34	.;T
Polyphen		0.0020	B;B
Vest4		0.017
MPC		0.0084
ClinPred		1.0	D
GERP RS		1.8
Varity_R		0.076
gMVP		0.13

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: rs12577167; hg19: chr11-5475118; COSMIC: COSV58298239;