14-21570435-A-G

Position:

• chr14-21570435-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001005465.2(OR10G3):​c.310T>C​(p.Phe104Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,613,416 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: OR10G3 NM_001005465.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86

Genes affected

OR10G3 (HGNC:8171): (olfactory receptor family 10 subfamily G member 3) 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026694715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR10G3	NM_001005465.2	c.310T>C	p.Phe104Leu	missense_variant	2/2	ENST00000641040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR10G3	ENST00000641040.1	c.310T>C	p.Phe104Leu	missense_variant	2/2		NM_001005465.2	P1
OR10G3	ENST00000641185.1	c.310T>C	p.Phe104Leu	missense_variant	3/3			P1
OR10G3	ENST00000641655.1	n.292-354T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000239 AC: 60 AN: 251374 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135856

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000166 AC: 242 AN: 1461150 Hom.: 0 Cov.: 65 AF XY: 0.000176 AC XY: 128 AN XY: 726850

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00187

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000505

Gnomad4 NFE exome AF: 0.000119

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74450

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000178

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

Aug 23, 2021

The c.310T>C (p.F104L) alteration is located in exon 1 (coding exon 1) of the OR10G3 gene. This alteration results from a T to C substitution at nucleotide position 310, causing the phenylalanine (F) at amino acid position 104 to be replaced by a leucine (L). 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	0.54
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T;T;T
Eigen	Benign	0.095
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.85	.;.;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.027	T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.3	L;L;L
MutationTaster	Benign	0.73	D
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.9	.;.;D
REVEL	Benign	0.096
Sift	Uncertain	0.0060	.;.;D
Sift4G	Uncertain	0.015	.;.;D
Polyphen		0.75	P;P;P
Vest4		0.22
MutPred		0.26		Loss of catalytic residue at F104 (P = 0.1182);Loss of catalytic residue at F104 (P = 0.1182);Loss of catalytic residue at F104 (P = 0.1182);
MVP		0.39
MPC		0.11
ClinPred		0.50	D
GERP RS		3.3
Varity_R		0.46
gMVP		0.067

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: rs142424951; hg19: chr14-22038566;