6-29440751-A-T

Variant names:

• chr6-29440751-A-T
• rs2074464
• NM_013941.4:c.736A>T

Variant summary

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

The NM_013941.4(OR10C1):​c.736A>T​(p.Met246Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0229 in 1,613,746 control chromosomes in the GnomAD database, including 1,173 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. M246V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.051 (380 hom., cov: 32)
  • Exomes 𝑓: 0.020 (793 hom.)
• Consequence: OR10C1 NM_013941.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.538

Genes affected

OR10C1 (HGNC:8165): (olfactory receptor family 10 subfamily C member 1) 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. This olfactory receptor gene is a segregating pseudogene, where some individuals have an allele that encodes a functional olfactory receptor, while other individuals have an allele encoding a protein that is predicted to be non-functional. [provided by RefSeq, Jul 2015]

OR11A1 (HGNC:8176): (olfactory receptor family 11 subfamily A member 1) 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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002963245).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR10C1	NM_013941.4	c.736A>T	p.Met246Leu	missense_variant	Exon 1 of 1	ENST00000444197.3	NP_039229.3
OR11A1	NM_001394828.1	c.-388-8764T>A		intron_variant	Intron 1 of 4	ENST00000377149.5	NP_001381757.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR10C1	ENST00000444197.3	c.736A>T	p.Met246Leu	missense_variant	Exon 1 of 1	6	NM_013941.4	ENSP00000419119.1
OR11A1	ENST00000377149.5	c.-388-8764T>A		intron_variant	Intron 1 of 4	6	NM_001394828.1	ENSP00000366354.1
OR10C1	ENST00000622521.1	c.742A>T	p.Met248Leu	missense_variant	Exon 1 of 1	6		ENSP00000481429.1

Frequencies

GnomAD3 genomes AF: 0.0506 AC: 7689 AN: 151994 Hom.: 378 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0637

Gnomad ASJ AF: 0.0741

Gnomad EAS AF: 0.0392

Gnomad SAS AF: 0.0193

Gnomad FIN AF: 0.00435

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0636

GnomAD3 exomes AF: 0.0281 AC: 7005 AN: 248988 Hom.: 229 AF XY: 0.0254 AC XY: 3431 AN XY: 134998

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0467

Gnomad ASJ exome AF: 0.0728

Gnomad EAS exome AF: 0.0155

Gnomad SAS exome AF: 0.0181

Gnomad FIN exome AF: 0.00490

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0334

GnomAD4 exome AF: 0.0201 AC: 29319 AN: 1461632 Hom.: 793 Cov.: 43 AF XY: 0.0200 AC XY: 14573 AN XY: 727136

Gnomad4 AFR exome AF: 0.127

Gnomad4 AMR exome AF: 0.0482

Gnomad4 ASJ exome AF: 0.0715

Gnomad4 EAS exome AF: 0.0664

Gnomad4 SAS exome AF: 0.0200

Gnomad4 FIN exome AF: 0.00464

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.0304

GnomAD4 genome AF: 0.0507 AC: 7715 AN: 152114 Hom.: 380 Cov.: 32 AF XY: 0.0489 AC XY: 3636 AN XY: 74348

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0637

Gnomad4 ASJ AF: 0.0741

Gnomad4 EAS AF: 0.0393

Gnomad4 SAS AF: 0.0191

Gnomad4 FIN AF: 0.00435

Gnomad4 NFE AF: 0.0144

Gnomad4 OTH AF: 0.0625

Alfa AF: 0.00159 Hom.: 40024

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0112 AC: 43

ExAC AF: 0.0279 AC: 3381

EpiCase AF: 0.0202

EpiControl AF: 0.0204

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.00065	T;.
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.27	N;.
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.030	N;.
REVEL	Benign	0.074
Sift	Uncertain	0.0020	D;.
Polyphen		0.0010	B;.
MutPred		0.46		Gain of catalytic residue at M246 (P = 0.003);.;
MPC		0.32
ClinPred		0.0094	T
GERP RS		3.5
Varity_R		0.39
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2074464; hg19: chr6-29408528;