9-122567801-A-T

Position:

• chr9-122567801-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001004454.2(OR1L8):​c.677T>A​(p.Val226Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OR1L8 NM_001004454.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

Genes affected

OR1L8 (HGNC:15110): (olfactory receptor family 1 subfamily L 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]

ENSG00000234156 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR1L8	NM_001004454.2	c.677T>A	p.Val226Asp	missense_variant	5/5	ENST00000641027.1	NP_001004454.1
OR1L8	XM_017014285.2	c.677T>A	p.Val226Asp	missense_variant	3/4		XP_016869774.1
OR1L8	XM_017014286.2	c.677T>A	p.Val226Asp	missense_variant	2/2		XP_016869775.1
OR1J2	XR_007061271.1	n.1541-12152A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR1L8	ENST00000641027.1	c.677T>A	p.Val226Asp	missense_variant	5/5		NM_001004454.2	ENSP00000493411.1
ENSG00000234156	ENST00000431442.2	n.1363-38845A>T		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Dec 07, 2024

The c.677T>A (p.V226D) alteration is located in exon 1 (coding exon 1) of the OR1L8 gene. This alteration results from a T to A substitution at nucleotide position 677, causing the valine (V) at amino acid position 226 to be replaced by an aspartic acid (D). 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	0.24
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.16	T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	.;D
M_CAP	Benign	0.0025	T
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	4.2	H;H
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-6.4	.;D
REVEL	Benign	0.22
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		0.88	P;P
Vest4		0.51
MutPred		0.76		Gain of disorder (P = 0.0138);Gain of disorder (P = 0.0138);
MVP		0.62
MPC		0.48
ClinPred		0.84	D
GERP RS		4.5
Varity_R		0.98
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-125330080;