11-55651364-C-T

Variant names:

• chr11-55651364-C-T
• rs370619125
• NM_001004059.3:c.461C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001004059.3(OR4S2):​c.461C>T​(p.Ser154Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000746 in 1,341,282 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S154Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: OR4S2 NM_001004059.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.818
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004059.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR4S2	NM_001004059.3	MANE Select	c.461C>T	p.Ser154Phe	missense	Exon 2 of 2	NP_001004059.2	A0A126GVG1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OR4S2	ENST00000641692.1	MANE Select	c.461C>T	p.Ser154Phe	missense	Exon 2 of 2	ENSP00000493389.1	Q8NH73

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.00000437 AC: 1 AN: 228644 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 7.46e-7 AC: 1 AN: 1341282 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 668056

African (AFR) AF: 0.00 AC: 0 AN: 32748

American (AMR) AF: 0.0000267 AC: 1 AN: 37452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24356

East Asian (EAS) AF: 0.00 AC: 0 AN: 34458

South Asian (SAS) AF: 0.00 AC: 0 AN: 80414

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5000

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1023124

Other (OTH) AF: 0.00 AC: 0 AN: 55548

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0067	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0060	T
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		0.82
PrimateAI	Benign	0.22	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.27
MutPred		0.75		Gain of helix (P = 0.132)
MVP		0.72
MPC		0.051
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.82
gMVP		0.62
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370619125; hg19: chr11-55418840;