11-5947996-T-G

Variant names:

• chr11-5947996-T-G
• rs761528471
• NM_001003443.3:c.650T>G

Variant summary

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

The NM_001003443.3(OR56A3):​c.650T>G​(p.Leu217Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L217P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: OR56A3 NM_001003443.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.88

Genes affected

OR56A3 (HGNC:14786): (olfactory receptor family 56 subfamily A member 3) 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, 0.962

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR56A3	NM_001003443.3	c.650T>G	p.Leu217Arg	missense_variant	Exon 3 of 3	ENST00000641160.1	NP_001003443.2
OR56A3	XM_047426926.1	c.650T>G	p.Leu217Arg	missense_variant	Exon 3 of 6		XP_047282882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR56A3	ENST00000641160.1	c.650T>G	p.Leu217Arg	missense_variant	Exon 3 of 3		NM_001003443.3	ENSP00000493059.1
OR56A3	ENST00000641905.1	c.650T>G	p.Leu217Arg	missense_variant	Exon 4 of 4			ENSP00000493319.1
OR56A3	ENST00000641878.1	n.402-691T>G		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.92	.;.;D
M_CAP	Benign	0.0086	T
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.052	D
MutationAssessor	Pathogenic	4.1	H;H;H
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-5.5	.;.;D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	.;.;D
Sift4G	Pathogenic	0.0010	.;.;D
Polyphen		1.0	D;D;D
Vest4		0.73
MutPred		0.81		Gain of MoRF binding (P = 0.0212);Gain of MoRF binding (P = 0.0212);Gain of MoRF binding (P = 0.0212);
MVP		0.85
MPC		0.54
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs761528471; hg19: chr11-5969226;