9-122553584-C-T

Position:

• chr9-122553584-C-T

Variant summary

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

The NM_001004457.2(OR1N2):​c.373C>T​(p.Arg125Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,614,008 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (21 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: OR1N2 NM_001004457.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.24

Genes affected

OR1N2 (HGNC:15111): (olfactory receptor family 1 subfamily N 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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008833498).
• BP6: Variant 9-122553584-C-T is Benign according to our data. Variant chr9-122553584-C-T is described in ClinVar as [Benign]. Clinvar id is 709559.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 = 0.00932 (1418/152182) while in subpopulation AFR AF= 0.0325 (1349/41506). AF 95% confidence interval is 0.0311. There are 21 homozygotes in gnomad4. There are 639 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR1N2	NM_001004457.2	c.373C>T	p.Arg125Cys	missense_variant	1/1	ENST00000373688.3
OR1L8	XM_017014285.2	c.*23-7055G>A		intron_variant
OR1J2	XR_007061271.1	n.1541-26369C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR1N2	ENST00000373688.3	c.373C>T	p.Arg125Cys	missense_variant	1/1		NM_001004457.2	P1
	ENST00000431442.2	n.1362+50714C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00933 AC: 1418 AN: 152064 Hom.: 21 Cov.: 31

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00248 AC: 621 AN: 250802 Hom.: 8 AF XY: 0.00176 AC XY: 239 AN XY: 135504

Gnomad AFR exome AF: 0.0327

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00105 AC: 1536 AN: 1461826 Hom.: 23 Cov.: 40 AF XY: 0.000891 AC XY: 648 AN XY: 727210

Gnomad4 AFR exome AF: 0.0355

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00195

GnomAD4 genome AF: 0.00932 AC: 1418 AN: 152182 Hom.: 21 Cov.: 31 AF XY: 0.00859 AC XY: 639 AN XY: 74410

Gnomad4 AFR AF: 0.0325

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00148 Hom.: 7

Bravo AF: 0.0104

ESP6500AA AF: 0.0350 AC: 154

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00315 AC: 383

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

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	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 24, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.066	.;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.70	T;T
MetaRNN	Benign	0.0088	T;T
MetaSVM	Uncertain	-0.072	T
MutationAssessor	Uncertain	2.3	.;M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.21	T
REVEL	Uncertain	0.38
Polyphen		1.0	.;D
MVP		0.85
MPC		0.65
ClinPred		0.059	T
GERP RS		4.5
Varity_R		0.41
gMVP		0.57

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: rs114238765; hg19: chr9-125315863; COSMIC: COSV65461103;