14-19921075-T-G

Variant names:

• chr14-19921075-T-G
• rs752052817
• NM_001005483.1:c.469T>G

Variant summary

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

The NM_001005483.1(OR4K5):​c.469T>G​(p.Leu157Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 36)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: OR4K5 NM_001005483.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.29

Genes affected

OR4K5 (HGNC:14745): (olfactory receptor family 4 subfamily K member 5) 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]

OR4K1 (HGNC:14726): (olfactory receptor family 4 subfamily K 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]

LOC124903278 (HGNC:):

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=0.021818787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR4K5	NM_001005483.1	c.469T>G	p.Leu157Val	missense_variant	Exon 1 of 1	ENST00000315915.5	NP_001005483.1
OR4K1	XM_011537153.3	c.-122+763T>G		intron_variant	Intron 1 of 2		XP_011535455.1
LOC124903278	XR_007064055.1	n.166-13993A>C		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR4K5	ENST00000315915.5	c.469T>G	p.Leu157Val	missense_variant	Exon 1 of 1	6	NM_001005483.1	ENSP00000319511.3

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251172 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461844 Hom.: 0 Cov.: 32 AF XY: 0.0000220 AC XY: 16 AN XY: 727218

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome Cov.: 36

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.469T>G (p.L157V) alteration is located in exon 1 (coding exon 1) of the OR4K5 gene. This alteration results from a T to G substitution at nucleotide position 469, causing the leucine (L) at amino acid position 157 to be replaced by a valine (V). 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	0.082
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.18
DANN	Benign	0.35
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.00066	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.43	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.055
Sift	Benign	1.0	T
Sift4G	Benign	0.87	T
Polyphen		0.0010	B
Vest4		0.010
MutPred		0.35		Gain of catalytic residue at F162 (P = 0);
MVP		0.17
MPC		0.0015
ClinPred		0.057	T
GERP RS		-3.9
Varity_R		0.040
gMVP		0.042

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs752052817; hg19: chr14-20389234;