1-247712583-G-T

Variant names:

• chr1-247712583-G-T
• NM_001005286.2:c.173C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001005286.2(OR6F1):​c.173C>A​(p.Pro58His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P58A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OR6F1 NM_001005286.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.46
• Publications: 0 publications found

Genes affected

OR6F1 (HGNC:15027): (olfactory receptor family 6 subfamily F 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]

ENSG00000239395 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR6F1	NM_001005286.2	c.173C>A	p.Pro58His	missense_variant	Exon 3 of 3	ENST00000641470.1	NP_001005286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR6F1	ENST00000641470.1	c.173C>A	p.Pro58His	missense_variant	Exon 3 of 3		NM_001005286.2	ENSP00000493342.1
ENSG00000239395	ENST00000419891.1	c.*38-496C>A		intron_variant	Intron 2 of 2	3		ENSP00000493458.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.173C>A (p.P58H) alteration is located in exon 1 (coding exon 1) of the OR6F1 gene. This alteration results from a C to A substitution at nucleotide position 173, causing the proline (P) at amino acid position 58 to be replaced by a histidine (H). 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	0.44
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	T;T;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;.;D
M_CAP	Benign	0.0022	T
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Pathogenic	4.4	H;H;H
PhyloP100		5.5
PrimateAI	Benign	0.21	T
PROVEAN	Pathogenic	-7.1	.;.;D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	.;.;D
Sift4G	Pathogenic	0.0010	.;.;D
Polyphen		1.0	D;D;D
Vest4		0.72
MutPred		0.75		Gain of catalytic residue at P58 (P = 0.0533);Gain of catalytic residue at P58 (P = 0.0533);Gain of catalytic residue at P58 (P = 0.0533);
MVP		0.79
MPC		0.61
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.90
gMVP		0.27
Mutation Taster		=56/44	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

hg19: chr1-247875885;