11-56490997-A-T

Variant names:

• chr11-56490997-A-T
• rs767188831
• NM_001005282.1:c.374T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001005282.1(OR5M8):​c.374T>A​(p.Ile125Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000493 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: OR5M8 NM_001005282.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.22

Genes affected

OR5M8 (HGNC:14846): (olfactory receptor family 5 subfamily M member 8) 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR5M8	NM_001005282.1	c.374T>A	p.Ile125Asn	missense_variant	Exon 1 of 1	ENST00000327216.5	NP_001005282.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR5M8	ENST00000327216.5	c.374T>A	p.Ile125Asn	missense_variant	Exon 1 of 1	6	NM_001005282.1	ENSP00000323354.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000756 AC: 19 AN: 251464 Hom.: 0 AF XY: 0.000132 AC XY: 18 AN XY: 135910

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 SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.0000688 AC XY: 50 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000765

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374T>A (p.I125N) alteration is located in exon 1 (coding exon 1) of the OR5M8 gene. This alteration results from a T to A substitution at nucleotide position 374, causing the isoleucine (I) at amino acid position 125 to be replaced by an asparagine (N). 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	0.33
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	4.2	H
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.84
MutPred		0.56		Loss of catalytic residue at L130 (P = 0.0251);
MVP		0.83
MPC		0.013
ClinPred		0.88	D
GERP RS		4.4
Varity_R		0.87
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs767188831; hg19: chr11-56258473;