6-29427340-T-C

Position:

• chr6-29427340-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001394828.1(OR11A1):​c.302A>G​(p.Gln101Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,802 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: 0.0000062 (0 hom.)
• Consequence: OR11A1 NM_001394828.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.23

Genes affected

OR11A1 (HGNC:8176): (olfactory receptor family 11 subfamily A 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]

OR5V1 (HGNC:13972): (olfactory receptor family 5 subfamily V 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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR11A1	NM_001394828.1	c.302A>G	p.Gln101Arg	missense_variant	5/5	ENST00000377149.5	NP_001381757.1
OR11A1	NM_001394829.1	c.302A>G	p.Gln101Arg	missense_variant	2/2		NP_001381758.1
OR11A1	NM_013937.4	c.302A>G	p.Gln101Arg	missense_variant	2/2		NP_039225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR11A1	ENST00000377149.5	c.302A>G	p.Gln101Arg	missense_variant	5/5	6	NM_001394828.1	ENSP00000366354.1
OR11A1	ENST00000377148.5	c.302A>G	p.Gln101Arg	missense_variant	2/2	6		ENSP00000366353.1
OR11A1	ENST00000641152.2	c.302A>G	p.Gln101Arg	missense_variant	2/2			ENSP00000493093.1
OR5V1	ENST00000377154.1	c.-196-4278A>G		intron_variant		6		ENSP00000366359.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000325 AC: 8 AN: 246520 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460802 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726718

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 26, 2024

The c.302A>G (p.Q101R) alteration is located in exon 1 (coding exon 1) of the OR11A1 gene. This alteration results from a A to G substitution at nucleotide position 302, causing the glutamine (Q) at amino acid position 101 to be replaced by an arginine (R). 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	0.55
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T;T;T;T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.0077	T
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	4.0	H;H;H;H
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.9	D;D;.;D
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.75
MutPred		0.80		Gain of methylation at Q101 (P = 0.1376);Gain of methylation at Q101 (P = 0.1376);Gain of methylation at Q101 (P = 0.1376);Gain of methylation at Q101 (P = 0.1376);
MVP		0.37
MPC		0.65
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.55
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs1466484441; hg19: chr6-29395117;