NM_001004754.3:c.176T>C

Variant names:

• chr11-5453664-T-C
• rs74049540
• NM_001004754.3:c.176T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001004754.3(OR51I2):​c.176T>C​(p.Met59Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00935 in 1,613,466 control chromosomes in the GnomAD database, including 1,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (634 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (583 hom.)
• Consequence: OR51I2 NM_001004754.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.08
• Publications: 6 publications found

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]

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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025898516).
• BP6: Variant 11-5453664-T-C is Benign according to our data. Variant chr11-5453664-T-C is described in ClinVar as Benign. ClinVar VariationId is 1289823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004754.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR51I2	NM_001004754.3	MANE Select	c.176T>C	p.Met59Thr	missense	Exon 2 of 2	NP_001004754.1	A0A126GVE9
	OR51B5	NM_001005567.3		c.-360+51905A>G		intron	N/A	NP_001005567.2	Q9H339
	OR51B5	NR_038321.2		n.84+51905A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR51I2	ENST00000641930.1	MANE Select	c.176T>C	p.Met59Thr	missense	Exon 2 of 2	ENSP00000493016.1	Q9H344
	HBE1	ENST00000292896.3	TSL:1	c.-267+51905A>G		intron	N/A	ENSP00000292896.2	P02100
	HBE1	ENST00000380237.5	TSL:1	c.-310+51905A>G		intron	N/A	ENSP00000369586.1	P02100

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 7497 AN: 152084 Hom.: 632 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.0320

GnomAD2 exomes AF: 0.0129 AC: 3232 AN: 250488 AF XY: 0.00928

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.00829

Gnomad ASJ exome AF: 0.00321

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000477

Gnomad OTH exome AF: 0.00720

GnomAD4 exome AF: 0.00517 AC: 7562 AN: 1461264 Hom.: 583 Cov.: 45 AF XY: 0.00443 AC XY: 3221 AN XY: 726892

African (AFR) AF: 0.175 AC: 5864 AN: 33478

American (AMR) AF: 0.00956 AC: 427 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00334 AC: 87 AN: 26062

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000534 AC: 46 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.000307 AC: 341 AN: 1111700

Other (OTH) AF: 0.0125 AC: 752 AN: 60362

GnomAD4 genome AF: 0.0494 AC: 7519 AN: 152202 Hom.: 634 Cov.: 32 AF XY: 0.0474 AC XY: 3524 AN XY: 74422

African (AFR) AF: 0.172 AC: 7124 AN: 41508

American (AMR) AF: 0.0181 AC: 277 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 68006

Other (OTH) AF: 0.0317 AC: 67 AN: 2114

Alfa AF: 0.0185 Hom.: 450

Bravo AF: 0.0548

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.161 AC: 709

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0156 AC: 1895

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0061	T
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.1
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.013	D
Polyphen		0.97	D
Vest4		0.18
MPC		0.015
ClinPred		0.10	T
GERP RS		5.6
Varity_R		0.84
gMVP		0.30
Mutation Taster		=43/57	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs74049540; hg19: chr11-5474894;