11-55651427-A-C

Position:

• chr11-55651427-A-C

Variant summary

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

The NM_001004059.3(OR4S2):​c.524A>C​(p.Tyr175Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000037 in 1,352,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: OR4S2 NM_001004059.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.181

Genes affected

OR4S2 (HGNC:15183): (olfactory receptor family 4 subfamily S member 2) 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=0.23983929).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OR4S2	NM_001004059.3	c.524A>C	p.Tyr175Ser	missense_variant	2/2	ENST00000641692.1	NP_001004059.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OR4S2	ENST00000641692.1	c.524A>C	p.Tyr175Ser	missense_variant	2/2		NM_001004059.3	ENSP00000493389.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 0.00000370 AC: 5 AN: 1352738 Hom.: 0 Cov.: 30 AF XY: 0.00000149 AC XY: 1 AN XY: 673050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000289

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000715

GnomAD4 genome Cov.: 25

Bravo AF: 0.0000113

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 10, 2024

The c.524A>C (p.Y175S) alteration is located in exon 1 (coding exon 1) of the OR4S2 gene. This alteration results from a A to C substitution at nucleotide position 524, causing the tyrosine (Y) at amino acid position 175 to be replaced by a serine (S). 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	0.43
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	0.060
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.80	.;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;M
PrimateAI	Benign	0.19	T
PROVEAN	Pathogenic	-7.9	.;D
REVEL	Benign	0.18
Sift	Uncertain	0.0010	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		0.57	P;P
Vest4		0.54
MutPred		0.63		Loss of stability (P = 0.0568);Loss of stability (P = 0.0568);
MVP		0.30
MPC		0.11
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.96
gMVP		0.37

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: rs1858566609; hg19: chr11-55418903;