11-55665286-T-A

Position:

• chr11-55665286-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001004704.2(OR4C6):​c.120T>A​(p.Asn40Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: OR4C6 NM_001004704.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.750

Genes affected

OR4C6 (HGNC:14743): (olfactory receptor family 4 subfamily C member 6) 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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR4C6	NM_001004704.2	c.120T>A	p.Asn40Lys	missense_variant	2/2	ENST00000314259.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR4C6	ENST00000314259.5	c.120T>A	p.Asn40Lys	missense_variant	2/2		NM_001004704.2	P1
OR4C6	ENST00000690330.1	c.120T>A	p.Asn40Lys	missense_variant	1/1			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jan 30, 2024

The c.120T>A (p.N40K) alteration is located in exon 1 (coding exon 1) of the OR4C6 gene. This alteration results from a T to A substitution at nucleotide position 120, causing the asparagine (N) at amino acid position 40 to be replaced by a lysine (K). 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	0.41
BayesDel_addAF	Benign	0.0054	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.81	.;T
M_CAP	Benign	0.0094	T
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	4.3	H;H
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-5.4	D;.
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.51
MutPred		0.83		Gain of ubiquitination at N40 (P = 0.0311);Gain of ubiquitination at N40 (P = 0.0311);
MVP		0.83
MPC		0.0042
ClinPred		0.99	D
GERP RS		-1.3
Varity_R		0.87
gMVP		0.78

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-55432762;