chr11-55572218-C-T

Variant names:

• chr11-55572218-C-T
• rs768595930
• NM_001004701.2:c.91C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001004701.2(OR4C16):​c.91C>T​(p.Arg31Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,457,896 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: OR4C16 NM_001004701.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.10
• Publications: 10 publications found

Genes affected

OR4C16 (HGNC:15172): (olfactory receptor family 4 subfamily C member 16) 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. This olfactory receptor gene is a segregating pseudogene, where some individuals have an allele that encodes a functional olfactory receptor, while other individuals have an allele encoding a protein that is predicted to be non-functional. [provided by RefSeq, Jun 2015]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04916963).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OR4C16	NM_001004701.2	c.91C>T	p.Arg31Cys	missense_variant	Exon 1 of 1	ENST00000623907.1	NP_001004701.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OR4C16	ENST00000623907.1	c.91C>T	p.Arg31Cys	missense_variant	Exon 1 of 1	6	NM_001004701.2	ENSP00000485295.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251112 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 23 AN: 1457896 Hom.: 0 Cov.: 33 AF XY: 0.0000152 AC XY: 11 AN XY: 725560

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.0000224 AC: 1 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1108444

Other (OTH) AF: 0.0000166 AC: 1 AN: 60236

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000959 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

May 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.91C>T (p.R31C) alteration is located in exon 1 (coding exon 1) of the OR4C16 gene. This alteration results from a C to T substitution at nucleotide position 91, causing the arginine (R) at amino acid position 31 to be replaced by a cysteine (C). 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	-0.52	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.33
DANN	Benign	0.64
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-1.8	N
PhyloP100		-3.1
PrimateAI	Benign	0.20	T
Polyphen		0.12	B
MutPred		0.55		Gain of catalytic residue at L32 (P = 0.0165);
ClinPred		0.65	D
GERP RS		-6.8
PromoterAI		-0.0086	Neutral
Varity_R		0.071
gMVP		0.13
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs768595930; hg19: chr11-55339694; COSMIC: COSV58940480;