12-55551335-A-G

Position:

• chr12-55551335-A-G

Variant summary

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

The NM_001005494.2(OR6C4):​c.109A>G​(p.Ile37Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.987 in 1,613,816 control chromosomes in the GnomAD database, including 785,806 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.99 (74906 hom., cov: 30)
  • Exomes 𝑓: 0.99 (710900 hom.)
• Consequence: OR6C4 NM_001005494.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.20

Genes affected

OR6C4 (HGNC:19632): (olfactory receptor family 6 subfamily C 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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8176448E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR6C4	NM_001005494.2	c.109A>G	p.Ile37Val	missense_variant	2/2	ENST00000641569.1	NP_001005494.1
OR6C4	NM_001385975.1	c.109A>G	p.Ile37Val	missense_variant	2/2		NP_001372904.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR6C4	ENST00000641569.1	c.109A>G	p.Ile37Val	missense_variant	2/2		NM_001005494.2	ENSP00000493181	P1
	ENST00000556750.5	n.57+34080T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.992 AC: 150902 AN: 152134 Hom.: 74847 Cov.: 30

Gnomad AFR AF: 0.997

Gnomad AMI AF: 0.991

Gnomad AMR AF: 0.997

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 0.995

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.985

Gnomad OTH AF: 0.998

GnomAD3 exomes AF: 0.992 AC: 248727 AN: 250632 Hom.: 123424 AF XY: 0.993 AC XY: 134418 AN XY: 135432

Gnomad AFR exome AF: 0.997

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 0.999

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.999

Gnomad FIN exome AF: 0.993

Gnomad NFE exome AF: 0.986

Gnomad OTH exome AF: 0.993

GnomAD4 exome AF: 0.986 AC: 1441492 AN: 1461564 Hom.: 710900 Cov.: 42 AF XY: 0.987 AC XY: 717494 AN XY: 727102

Gnomad4 AFR exome AF: 0.998

Gnomad4 AMR exome AF: 0.996

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 0.993

Gnomad4 NFE exome AF: 0.983

Gnomad4 OTH exome AF: 0.989

GnomAD4 genome AF: 0.992 AC: 151020 AN: 152252 Hom.: 74906 Cov.: 30 AF XY: 0.993 AC XY: 73907 AN XY: 74448

Gnomad4 AFR AF: 0.997

Gnomad4 AMR AF: 0.997

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 0.995

Gnomad4 NFE AF: 0.985

Gnomad4 OTH AF: 0.998

Alfa AF: 0.988 Hom.: 153520

Bravo AF: 0.992

TwinsUK AF: 0.982 AC: 3642

ALSPAC AF: 0.984 AC: 3793

ESP6500AA AF: 0.997 AC: 4391

ESP6500EA AF: 0.986 AC: 8480

ExAC AF: 0.992 AC: 120490

Asia WGS AF: 0.999 AC: 3473 AN: 3476

EpiCase AF: 0.988

EpiControl AF: 0.988

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.3
DANN	Benign	0.79
DEOGEN2	Benign	0.0013	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.30	.;.;T
MetaRNN	Benign	0.0000018	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.12	N;N;N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.11	.;.;N
REVEL	Benign	0.056
Sift	Benign	1.0	.;.;T
Sift4G	Benign	1.0	.;.;T
Polyphen		0.0	B;B;B
Vest4		0.016
MPC		0.0017
ClinPred		0.0040	T
GERP RS		1.8
Varity_R		0.028
gMVP		0.025

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: rs7313899; hg19: chr12-55945119;