NM_001004059.3:c.437C>T

Variant names:

• chr11-55651340-C-T
• rs778705235
• NM_001004059.3:c.437C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001004059.3(OR4S2):​c.437C>T​(p.Thr146Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,483,726 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000065 (2 hom., cov: 25)
  • Exomes 𝑓: 0.00015 (31 hom.)
• Consequence: OR4S2 NM_001004059.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.160
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26462397).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.437C>T	p.Thr146Met	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.437C>T	p.Thr146Met	missense	Exon 2 of 2	ENSP00000493389.1	Q8NH73

Frequencies

GnomAD3 genomes AF: 0.0000653 AC: 9 AN: 137920 Hom.: 2 Cov.: 25

Gnomad AFR AF: 0.000101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000805

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000525 AC: 12 AN: 228638 AF XY: 0.0000727

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000638

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000857

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000153 AC: 206 AN: 1345806 Hom.: 31 Cov.: 29 AF XY: 0.000137 AC XY: 92 AN XY: 669992

African (AFR) AF: 0.00 AC: 0 AN: 32784

American (AMR) AF: 0.00 AC: 0 AN: 37432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24378

East Asian (EAS) AF: 0.000145 AC: 5 AN: 34506

South Asian (SAS) AF: 0.0000248 AC: 2 AN: 80508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5030

European-Non Finnish (NFE) AF: 0.000192 AC: 197 AN: 1027320

Other (OTH) AF: 0.0000359 AC: 2 AN: 55674

GnomAD4 genome AF: 0.0000653 AC: 9 AN: 137920 Hom.: 2 Cov.: 25 AF XY: 0.0000449 AC XY: 3 AN XY: 66852

African (AFR) AF: 0.000101 AC: 4 AN: 39744

American (AMR) AF: 0.00 AC: 0 AN: 12618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3210

East Asian (EAS) AF: 0.00 AC: 0 AN: 4176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8958

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000805 AC: 5 AN: 62118

Other (OTH) AF: 0.00 AC: 0 AN: 1832

Alfa AF: 0.0000732 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000433 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0039	T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.048
FATHMM_MKL	Benign	0.054	N
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.16
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.14
MutPred		0.41		Loss of catalytic residue at T146 (P = 0.1215)
MVP		0.60
MPC		0.26
ClinPred		0.21	T
GERP RS		4.4
Varity_R		0.14
gMVP		0.39
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs778705235; hg19: chr11-55418816;