14-19781050-A-G

Position:

• chr14-19781050-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001005500.2(OR4M1):​c.728A>G​(p.Tyr243Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000692 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 36)
  • Exomes 𝑓: 0.00073 (0 hom.)
• Consequence: OR4M1 NM_001005500.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.530

Genes affected

OR4M1 (HGNC:14735): (olfactory receptor family 4 subfamily M 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]

OR4N2 (HGNC:14742): (olfactory receptor family 4 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 seven-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, Mar 2014]

OR4M1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058675796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR4M1	NM_001005500.2	c.728A>G	p.Tyr243Cys	missense_variant	2/2	ENST00000641200.1	NP_001005500.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR4M1	ENST00000641200.1	c.728A>G	p.Tyr243Cys	missense_variant	2/2		NM_001005500.2	ENSP00000492985.1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152208 Hom.: 0 Cov.: 36

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000720

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000450 AC: 113 AN: 251390 Hom.: 0 AF XY: 0.000442 AC XY: 60 AN XY: 135878

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000879

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000726 AC: 1062 AN: 1461808 Hom.: 0 Cov.: 34 AF XY: 0.000697 AC XY: 507 AN XY: 727210

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000882

Gnomad4 OTH exome AF: 0.000960

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152208 Hom.: 0 Cov.: 36 AF XY: 0.000336 AC XY: 25 AN XY: 74346

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000551 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000502 AC: 61

EpiCase AF: 0.00109

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.728A>G (p.Y243C) alteration is located in exon 1 (coding exon 1) of the OR4M1 gene. This alteration results from a A to G substitution at nucleotide position 728, causing the tyrosine (Y) at amino acid position 243 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.00094	T;T
Eigen	Benign	-0.054
Eigen_PC	Benign	-0.060
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.78	.;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.059	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.36	.;N
REVEL	Benign	0.28
Sift	Uncertain	0.0050	.;D
Sift4G	Uncertain	0.0070	.;D
Polyphen		0.99	D;D
Vest4		0.43
MVP		0.70
MPC		0.0064
ClinPred		0.089	T
GERP RS		3.2
Varity_R		0.13
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs146706497; hg19: chr14-20249209;