11-124310012-A-T

Variant names:

• chr11-124310012-A-T
• rs761004797
• NM_001002917.2:c.755T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001002917.2(OR8D1):​c.755T>A​(p.Phe252Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F252S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: OR8D1 NM_001002917.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.849
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043055266).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002917.2. 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
	OR8D1	NM_001002917.2	MANE Select	c.755T>A	p.Phe252Tyr	missense	Exon 3 of 3	NP_001002917.1	A0A126GVG6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR8D1	ENST00000641015.1	MANE Select	c.755T>A	p.Phe252Tyr	missense	Exon 3 of 3	ENSP00000493365.1	Q8WZ84
	OR8D1	ENST00000357821.2	TSL:6	c.755T>A	p.Phe252Tyr	missense	Exon 1 of 1	ENSP00000350474.2	Q8WZ84
	OR8D1	ENST00000641897.1		c.755T>A	p.Phe252Tyr	missense	Exon 4 of 4	ENSP00000493091.1	Q8WZ84

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449500 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 720182

⚠️ 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: 32942

American (AMR) AF: 0.00 AC: 0 AN: 43240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25088

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 84410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52884

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5662

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105972

Other (OTH) AF: 0.00 AC: 0 AN: 59752

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.9
DANN	Benign	0.68
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.96	N
PhyloP100		-0.85
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.044
Sift	Benign	0.61	T
Sift4G	Benign	1.0	T
Polyphen		0.0030	B
Vest4		0.13
MutPred		0.55		Gain of catalytic residue at F252 (P = 0.1846)
MVP		0.15
MPC		0.17
ClinPred		0.13	T
GERP RS		-0.23
Varity_R		0.091
gMVP		0.11
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs761004797; hg19: chr11-124179908;