chr14-20640749-C-T

Variant names:

• chr14-20640749-C-T
• rs754271484
• NM_001001968.1:c.943G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001001968.1(OR6S1):​c.943G>A​(p.Val315Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,605,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: OR6S1 NM_001001968.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.170
• Publications: 2 publications found

Genes affected

OR6S1 (HGNC:15363): (olfactory receptor family 6 subfamily S 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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037647843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR6S1	NM_001001968.1	c.943G>A	p.Val315Ile	missense_variant	Exon 1 of 1	ENST00000320704.3	NP_001001968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR6S1	ENST00000320704.3	c.943G>A	p.Val315Ile	missense_variant	Exon 1 of 1	6	NM_001001968.1	ENSP00000313110.3

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150394 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000666

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000398 AC: 10 AN: 251146 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

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: 0.000163

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1454662 Hom.: 0 Cov.: 36 AF XY: 0.00000829 AC XY: 6 AN XY: 723678

African (AFR) AF: 0.00 AC: 0 AN: 33258

American (AMR) AF: 0.000225 AC: 10 AN: 44464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25798

East Asian (EAS) AF: 0.00 AC: 0 AN: 39176

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86170

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52906

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1107250

Other (OTH) AF: 0.0000501 AC: 3 AN: 59912

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150394 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 73248

African (AFR) AF: 0.00 AC: 0 AN: 40944

American (AMR) AF: 0.0000666 AC: 1 AN: 15020

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67768

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.943G>A (p.V315I) alteration is located in exon 1 (coding exon 1) of the OR6S1 gene. This alteration results from a G to A substitution at nucleotide position 943, causing the valine (V) at amino acid position 315 to be replaced by an isoleucine (I). 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	0.073
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.074
DANN	Benign	0.29
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.17
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.020	N
REVEL	Benign	0.011
Sift	Benign	0.65	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.066
MVP		0.081
MPC		0.014
ClinPred		0.017	T
GERP RS		-2.8
Varity_R		0.025
gMVP		0.076
Mutation Taster		=100/0	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: rs754271484; hg19: chr14-21108908;