11-124309928-G-A

Variant names:

• chr11-124309928-G-A
• rs143558290
• NM_001002917.2:c.839C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001002917.2(OR8D1):​c.839C>T​(p.Thr280Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000554 in 1,533,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: OR8D1 NM_001002917.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.322

Genes affected

OR8D1 (HGNC:8481): (olfactory receptor family 8 subfamily D 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0885728).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR8D1	NM_001002917.2	c.839C>T	p.Thr280Met	missense_variant	Exon 3 of 3	ENST00000641015.1	NP_001002917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR8D1	ENST00000641015.1	c.839C>T	p.Thr280Met	missense_variant	Exon 3 of 3		NM_001002917.2	ENSP00000493365.1
OR8D1	ENST00000357821.2	c.839C>T	p.Thr280Met	missense_variant	Exon 1 of 1	6		ENSP00000350474.2
OR8D1	ENST00000641897.1	c.839C>T	p.Thr280Met	missense_variant	Exon 4 of 4			ENSP00000493091.1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152018 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000323 AC: 6 AN: 185682 Hom.: 0 AF XY: 0.0000408 AC XY: 4 AN XY: 97928

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000183

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000224

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000507 AC: 70 AN: 1381438 Hom.: 0 Cov.: 30 AF XY: 0.0000574 AC XY: 39 AN XY: 679482

Gnomad4 AFR exome AF: 0.000130

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000384

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000344

Gnomad4 OTH exome AF: 0.0000703

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74346

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000332 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.839C>T (p.T280M) alteration is located in exon 1 (coding exon 1) of the OR8D1 gene. This alteration results from a C to T substitution at nucleotide position 839, causing the threonine (T) at amino acid position 280 to be replaced by a methionine (M). 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	0.097
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0058	T;T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.0068	N
LIST_S2	Benign	0.76	.;.;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.089	T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.99	L;L;L
PrimateAI	Benign	0.16	T
PROVEAN	Benign	-1.7	.;.;N
REVEL	Benign	0.050
Sift	Uncertain	0.022	.;.;D
Sift4G	Benign	0.14	.;.;T
Polyphen		0.99	D;D;D
Vest4		0.19
MVP		0.26
MPC		0.15
ClinPred		0.052	T
GERP RS		1.3
Varity_R		0.033
gMVP		0.092

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: rs143558290; hg19: chr11-124179824;