19-8731436-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001004699.3(OR2Z1):c.408G>C(p.Met136Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: OR2Z1 NM_001004699.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13

Genes affected

OR2Z1 (HGNC:15391): (olfactory receptor family 2 subfamily Z 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR2Z1	NM_001004699.3	c.408G>C	p.Met136Ile	missense_variant	3/3	ENST00000641125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR2Z1	ENST00000641125.1	c.408G>C	p.Met136Ile	missense_variant	3/3		NM_001004699.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461888 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

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

Jan 06, 2023

The c.408G>C (p.M136I) alteration is located in exon 1 (coding exon 1) of the OR2Z1 gene. This alteration results from a G to C substitution at nucleotide position 408, causing the methionine (M) at amino acid position 136 to be replaced by an isoleucine (I). 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	Uncertain	0.48
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Benign	0.060	N
M_CAP	Benign	0.0027	T
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.50	N
PrimateAI	Uncertain	0.63	T
Polyphen		0.99	D;D
Vest4		0.29
MutPred		0.52		Loss of catalytic residue at Q131 (P = 0.2361);Loss of catalytic residue at Q131 (P = 0.2361);
MVP		0.63
MPC		0.24
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.67
gMVP		0.19

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: rs781997373; hg19: chr19-8841798;