14-19876496-G-A

Variant names:

• chr14-19876496-G-A
• rs141210026
• NM_001005501.2:c.229G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001005501.2(OR4K2):​c.229G>A​(p.Ala77Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,613,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 35)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: OR4K2 NM_001005501.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.933

Genes affected

OR4K2 (HGNC:14728): (olfactory receptor family 4 subfamily K 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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08043814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR4K2	NM_001005501.2	c.229G>A	p.Ala77Thr	missense_variant	Exon 2 of 2	ENST00000641885.1	NP_001005501.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR4K2	ENST00000641885.1	c.229G>A	p.Ala77Thr	missense_variant	Exon 2 of 2		NM_001005501.2	ENSP00000493007.1
OR4K2	ENST00000298642.2	c.229G>A	p.Ala77Thr	missense_variant	Exon 1 of 1	6		ENSP00000298642.2
OR4K2	ENST00000641522.1	n.1133+112G>A		intron_variant	Intron 2 of 2
OR4K2	ENST00000641785.1	n.1133+112G>A		intron_variant	Intron 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 151964 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000677 AC: 17 AN: 251286 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000968

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000101 AC: 148 AN: 1461758 Hom.: 0 Cov.: 35 AF XY: 0.000103 AC XY: 75 AN XY: 727172

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000987 AC: 15 AN: 151964 Hom.: 0 Cov.: 35 AF XY: 0.0000674 AC XY: 5 AN XY: 74210

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 0

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.229G>A (p.A77T) alteration is located in exon 1 (coding exon 1) of the OR4K2 gene. This alteration results from a G to A substitution at nucleotide position 229, causing the alanine (A) at amino acid position 77 to be replaced by a threonine (T). 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	0.17
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0024	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.095
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.82	.;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-1.4	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.54	.;N
REVEL	Benign	0.16
Sift	Benign	0.62	.;T
Sift4G	Benign	1.0	.;T
Polyphen		1.0	D;D
Vest4		0.035
MVP		0.37
MPC		.;5.97400648491E-4
ClinPred		0.22	T
GERP RS		4.4
Varity_R		0.11
gMVP		0.13

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: rs141210026; hg19: chr14-20344655; COSMIC: COSV100063939;