chr8-166645-C-A

Variant names:

• chr8-166645-C-A
• rs1278218122
• NM_001005504.1:c.380G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001005504.1(OR4F21):​c.380G>T​(p.Cys127Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000114 in 1,310,686 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C127R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., cov: 14)
  • Exomes 𝑓: 0.000011 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: OR4F21 NM_001005504.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.84
• Publications: 0 publications found

Genes affected

OR4F21 (HGNC:19583): (olfactory receptor family 4 subfamily F member 21) 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]

ENSG00000292979 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001005504.1. 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
	OR4F21	NM_001005504.1	MANE Select	c.380G>T	p.Cys127Phe	missense	Exon 1 of 1	NP_001005504.1	O95013

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR4F21	ENST00000320901.4	TSL:6 MANE Select	c.380G>T	p.Cys127Phe	missense	Exon 1 of 1	ENSP00000318878.3	O95013
	ENSG00000292979	ENST00000805562.1		n.115+65484G>T		intron	N/A
	ENSG00000292979	ENST00000805563.1		n.136+66331G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000183 AC: 2 AN: 109204 Hom.: 0 Cov.: 14

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000395

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000392 AC: 1 AN: 25516 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000104

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000114 AC: 15 AN: 1310686 Hom.: 2 Cov.: 28 AF XY: 0.0000168 AC XY: 11 AN XY: 653154

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31448

American (AMR) AF: 0.00 AC: 0 AN: 42280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25026

East Asian (EAS) AF: 0.00 AC: 0 AN: 34720

South Asian (SAS) AF: 0.00 AC: 0 AN: 74618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3850

European-Non Finnish (NFE) AF: 0.0000149 AC: 15 AN: 1006874

Other (OTH) AF: 0.00 AC: 0 AN: 54820

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000436687), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000183 AC: 2 AN: 109204 Hom.: 0 Cov.: 14 AF XY: 0.0000191 AC XY: 1 AN XY: 52242

African (AFR) AF: 0.00 AC: 0 AN: 31222

American (AMR) AF: 0.00 AC: 0 AN: 9924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2876

East Asian (EAS) AF: 0.00 AC: 0 AN: 2744

South Asian (SAS) AF: 0.00 AC: 0 AN: 2312

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 244

European-Non Finnish (NFE) AF: 0.0000395 AC: 2 AN: 50570

Other (OTH) AF: 0.00 AC: 0 AN: 1374

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0019	T
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-10	D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.60
MVP		0.49
ClinPred		0.99	D
GERP RS		2.0
PromoterAI		-0.0029	Neutral
Varity_R		0.93
gMVP		0.14
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1278218122; hg19: chr8-116645;