11-55665626-G-A

Position:

• chr11-55665626-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001004704.2(OR4C6):​c.460G>A​(p.Ala154Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,613,500 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (70 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (66 hom.)
• Consequence: OR4C6 NM_001004704.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.94

Genes affected

OR4C6 (HGNC:14743): (olfactory receptor family 4 subfamily C 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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003264606).
• BP6: Variant 11-55665626-G-A is Benign according to our data. Variant chr11-55665626-G-A is described in ClinVar as [Benign]. Clinvar id is 785347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (2056/152070) while in subpopulation AFR AF= 0.0458 (1898/41398). AF 95% confidence interval is 0.0441. There are 70 homozygotes in gnomad4. There are 959 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 70 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR4C6	NM_001004704.2	c.460G>A	p.Ala154Thr	missense_variant	2/2	ENST00000314259.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR4C6	ENST00000314259.5	c.460G>A	p.Ala154Thr	missense_variant	2/2		NM_001004704.2	P1
OR4C6	ENST00000690330.1	c.460G>A	p.Ala154Thr	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 2050 AN: 151954 Hom.: 70 Cov.: 32

Gnomad AFR AF: 0.0458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00860

GnomAD3 exomes AF: 0.00447 AC: 1124 AN: 251194 Hom.: 28 AF XY: 0.00350 AC XY: 475 AN XY: 135750

Gnomad AFR exome AF: 0.0465

Gnomad AMR exome AF: 0.00292

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000432

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00187 AC: 2736 AN: 1461430 Hom.: 66 Cov.: 32 AF XY: 0.00172 AC XY: 1248 AN XY: 727042

Gnomad4 AFR exome AF: 0.0483

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.0197

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000163

Gnomad4 OTH exome AF: 0.00441

GnomAD4 genome AF: 0.0135 AC: 2056 AN: 152070 Hom.: 70 Cov.: 32 AF XY: 0.0129 AC XY: 959 AN XY: 74340

Gnomad4 AFR AF: 0.0458

Gnomad4 AMR AF: 0.00393

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00851

Alfa AF: 0.00199 Hom.: 9

Bravo AF: 0.0156

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0436 AC: 192

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00504 AC: 612

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0088	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.83	.;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0070	D;.
Polyphen		1.0	D;D
Vest4		0.062
MVP		0.40
MPC		0.0056
ClinPred		0.039	T
GERP RS		2.9
Varity_R		0.18
gMVP		0.080

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: rs77072313; hg19: chr11-55433102;