11-5352021-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001004750.1(OR51B6):c.514C>T(p.Leu172Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.255 in 1,603,842 control chromosomes in the GnomAD database, including 54,593 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 5515 hom., cov: 32)

Exomes 𝑓: 0.25 ( 49078 hom. )

Consequence

OR51B6
NM_001004750.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.668

Publications

49 publications found

Variant links:

Genes affected

OR51B6 (HGNC:19600): (olfactory receptor family 51 subfamily B member 6) 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]

OR51B6 links:

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]

HBE1 links:

ENSG00000239920 (HGNC:):

ENSG00000239920 links:

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]

OR51B5 links:

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]

HBG2 Gene-Disease associations (from GenCC):

hemoglobinopathy Toms River
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary persistence of fetal hemoglobin-beta-thalassemia syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
cyanosis, transient neonatal
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

HBG2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068277717).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004750.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OR51B6	NM_001004750.1	MANE Select	c.514C>T	p.Leu172Phe	missense	Exon 1 of 1	NP_001004750.1	Q9H340
OR51B5	NM_001005567.3		c.-359-5111G>A		intron	N/A	NP_001005567.2	Q9H339
OR51B5	NR_038321.2		n.85-5111G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OR51B6	ENST00000380219.1	TSL:6 MANE Select	c.514C>T	p.Leu172Phe	missense	Exon 1 of 1	ENSP00000369568.1	Q9H340
HBE1	ENST00000292896.3	TSL:1	c.-266-81865G>A		intron	N/A	ENSP00000292896.2	P02100
HBE1	ENST00000380237.5	TSL:1	c.-309-70070G>A		intron	N/A	ENSP00000369586.1	P02100

Frequencies

GnomAD3 genomes

AF:

0.264

AC:

40104

AN:

151854

Hom.:

5505

Cov.:

show subpopulations

Gnomad AFR

AF:

0.308

Gnomad AMI

AF:

0.241

Gnomad AMR

AF:

0.237

Gnomad ASJ

AF:

0.254

Gnomad EAS

AF:

0.0646

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.256

Gnomad MID

AF:

0.193

Gnomad NFE

AF:

0.264

Gnomad OTH

AF:

0.261

GnomAD2 exomes

AF:

0.237

AC:

59344

AN:

250830

AF XY:

0.236

show subpopulations

Gnomad AFR exome

AF:

0.311

Gnomad AMR exome

AF:

0.216

Gnomad ASJ exome

AF:

0.252

Gnomad EAS exome

AF:

0.0611

Gnomad FIN exome

AF:

0.261

Gnomad NFE exome

AF:

0.257

Gnomad OTH exome

AF:

0.237

GnomAD4 exome

AF:

0.254

AC:

368522

AN:

1451870

Hom.:

49078

Cov.:

AF XY:

0.253

AC XY:

182702

AN XY:

722682

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.307

AC:

10206

AN:

33282

American (AMR)

AF:

0.219

AC:

9787

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.250

AC:

6503

AN:

26038

East Asian (EAS)

AF:

0.0551

AC:

2185

AN:

39674

South Asian (SAS)

AF:

0.227

AC:

19472

AN:

85968

European-Finnish (FIN)

AF:

0.257

AC:

13738

AN:

53354

Middle Eastern (MID)

AF:

0.192

AC:

1105

AN:

5750

European-Non Finnish (NFE)

AF:

0.263

AC:

290502

AN:

1103074

Other (OTH)

AF:

0.250

AC:

15024

AN:

60042

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.394

Heterozygous variant carriers

15132

30264

45396

60528

75660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9640

19280

28920

38560

48200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.264

AC:

40142

AN:

151972

Hom.:

5515

Cov.:

AF XY:

0.261

AC XY:

19420

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.308

AC:

12760

AN:

41422

American (AMR)

AF:

0.236

AC:

3609

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.254

AC:

882

AN:

3472

East Asian (EAS)

AF:

0.0641

AC:

332

AN:

5176

South Asian (SAS)

AF:

0.226

AC:

1090

AN:

4818

European-Finnish (FIN)

AF:

0.256

AC:

2700

AN:

10562

Middle Eastern (MID)

AF:

0.190

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.264

AC:

17946

AN:

67930

Other (OTH)

AF:

0.259

AC:

547

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1493

2986

4480

5973

7466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

416

832

1248

1664

2080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.257

Hom.:

21456

Bravo

AF:

0.263

TwinsUK

AF:

0.274

AC:

1017

ALSPAC

AF:

0.251

AC:

966

ESP6500AA

AF:

0.292

AC:

1285

ESP6500EA

AF:

0.264

AC:

2270

ExAC

AF:

0.239

AC:

28970

Asia WGS

AF:

0.212

AC:

739

AN:

3478

EpiCase

AF:

0.258

EpiControl

AF:

0.258

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.012

Eigen

Benign

0.13

Eigen_PC

Benign

-0.080

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0068

MetaSVM

Benign

-0.94

MutationAssessor

Pathogenic

3.5

PhyloP100

-0.67

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-3.9

REVEL

Benign

0.092

Sift

Uncertain

0.0050

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.14

MPC

0.013

ClinPred

0.049

GERP RS

3.3

Varity_R

0.79

gMVP

0.029

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over