11-59443173-C-T

Variant names:

• chr11-59443173-C-T
• rs138097107
• NM_001004728.2:c.5C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001004728.2(OR5A1):​c.5C>T​(p.Ser2Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000461 in 1,612,864 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00046 (6 hom.)
• Consequence: OR5A1 NM_001004728.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.150

Genes affected

OR5A1 (HGNC:8319): (olfactory receptor family 5 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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00785926).
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR5A1	NM_001004728.2	c.5C>T	p.Ser2Phe	missense_variant	Exon 2 of 2	ENST00000641045.1	NP_001004728.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR5A1	ENST00000641045.1	c.5C>T	p.Ser2Phe	missense_variant	Exon 2 of 2		NM_001004728.2	ENSP00000493195.1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152170 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000653 AC: 163 AN: 249792 Hom.: 0 AF XY: 0.000644 AC XY: 87 AN XY: 135030

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00887

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000657

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000453

Gnomad OTH exome AF: 0.000985

GnomAD4 exome AF: 0.000464 AC: 678 AN: 1460576 Hom.: 6 Cov.: 32 AF XY: 0.000464 AC XY: 337 AN XY: 726536

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00850

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000227

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152288 Hom.: 0 Cov.: 31 AF XY: 0.000470 AC XY: 35 AN XY: 74468

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000892 Hom.: 1

Bravo AF: 0.000582

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000535 AC: 65

EpiCase AF: 0.000436

EpiControl AF: 0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5C>T (p.S2F) alteration is located in exon 1 (coding exon 1) of the OR5A1 gene. This alteration results from a C to T substitution at nucleotide position 5, causing the serine (S) at amino acid position 2 to be replaced by a phenylalanine (F). 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	Benign	0.14
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.0080	T;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.40	.;T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.0079	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.3	.;N
REVEL	Benign	0.036
Sift	Benign	0.030	.;D
Sift4G	Uncertain	0.014	.;D
Polyphen		0.0010	B;B
Vest4		0.10
MVP		0.33
MPC		0.026
ClinPred		0.013	T
GERP RS		1.8
Varity_R		0.046
gMVP		0.14

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: rs138097107; hg19: chr11-59210646;