6-29426771-A-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.871T>G(p.Tyr291Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,788 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: 0.0000034 (0 hom.)
• Consequence: OR11A1 NM_001394828.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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, 0.983

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR11A1	NM_001394828.1	c.871T>G	p.Tyr291Asp	missense_variant	5/5	ENST00000377149.5
OR11A1	NM_001394829.1	c.871T>G	p.Tyr291Asp	missense_variant	2/2
OR11A1	NM_013937.4	c.871T>G	p.Tyr291Asp	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR11A1	ENST00000377149.5	c.871T>G	p.Tyr291Asp	missense_variant	5/5		NM_001394828.1	P1
OR11A1	ENST00000377148.5	c.871T>G	p.Tyr291Asp	missense_variant	2/2			P1
OR11A1	ENST00000641152.2	c.871T>G	p.Tyr291Asp	missense_variant	2/2			P1
OR5V1	ENST00000377154.1	c.-196-3709T>G		intron_variant				P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000812 AC: 2 AN: 246448 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.00000905

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460788 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726710

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000847 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

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 05, 2021

The c.871T>G (p.Y291D) 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 871, causing the tyrosine (Y) at amino acid position 291 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	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Benign	0.14	T;T;T;T
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Pathogenic	4.7	H;H;H;H
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-9.4	D;D;.;D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D;D;.;D
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	D;D;D;D
Vest4		0.80
MutPred		0.88		Gain of disorder (P = 0.0713);Gain of disorder (P = 0.0713);Gain of disorder (P = 0.0713);Gain of disorder (P = 0.0713);
MVP		0.56
MPC		0.85
ClinPred		1.0	D
GERP RS		3.3
Varity_R		0.89
gMVP		0.61

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: rs772347897; hg19: chr6-29394548;