6-29426915-A-C

Variant summary

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

The NM_001394828.1(OR11A1):c.727T>G(p.Ser243Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,460,762 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: OR11A1 NM_001394828.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.04

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 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=0.18855539).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR11A1	NM_001394828.1	c.727T>G	p.Ser243Ala	missense_variant	5/5	ENST00000377149.5
OR11A1	NM_001394829.1	c.727T>G	p.Ser243Ala	missense_variant	2/2
OR11A1	NM_013937.4	c.727T>G	p.Ser243Ala	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR11A1	ENST00000377149.5	c.727T>G	p.Ser243Ala	missense_variant	5/5		NM_001394828.1	P1
OR11A1	ENST00000377148.5	c.727T>G	p.Ser243Ala	missense_variant	2/2			P1
OR11A1	ENST00000641152.2	c.727T>G	p.Ser243Ala	missense_variant	2/2			P1
OR5V1	ENST00000377154.1	c.-196-3853T>G		intron_variant				P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000243 AC: 6 AN: 246458 Hom.: 0 AF XY: 0.0000298 AC XY: 4 AN XY: 134302

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1460762 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726706

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.000334 Hom.: 0

ExAC AF: 0.0000169 AC: 2

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

Oct 12, 2022

The c.727T>G (p.S243A) alteration is located in exon 1 (coding exon 1) of the OR11A1 gene. This alteration results from a T to G substitution at nucleotide position 727, causing the serine (S) at amino acid position 243 to be replaced by an alanine (A). 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	0.098
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0013	T;T;T;T
Eigen	Benign	-0.057
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.092	N
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;L;L
MutationTaster	Benign	1.0	N;N;N;D;D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.0	N;N;.;N
REVEL	Benign	0.18
Sift	Benign	0.083	T;T;.;T
Sift4G	Benign	0.29	T;T;.;T
Polyphen		1.0	D;D;D;D
Vest4		0.079
MutPred		0.54		Loss of disorder (P = 0.0617);Loss of disorder (P = 0.0617);Loss of disorder (P = 0.0617);Loss of disorder (P = 0.0617);
MVP		0.20
MPC		0.54
ClinPred		0.17	T
GERP RS		3.5
Varity_R		0.18
gMVP		0.029

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: rs747194461; hg19: chr6-29394692;