7-99877003-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001005276.1(OR2AE1):c.31G>C(p.Asp11His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: OR2AE1 NM_001005276.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38

Genes affected

OR2AE1 (HGNC:15087): (olfactory receptor family 2 subfamily AE 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]

TRIM4 (HGNC:16275): (tripartite motif containing 4) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to cytoplasmic bodies. Its function has not been identified. Alternatively spliced transcript variants that encode different isoforms have been described.[provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3070953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR2AE1	NM_001005276.1	c.31G>C	p.Asp11His	missense_variant	1/1	ENST00000316368.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR2AE1	ENST00000316368.3	c.31G>C	p.Asp11His	missense_variant	1/1		NM_001005276.1	P1
TRIM4	ENST00000447480.5	c.596G>C	p.Arg199Thr	missense_variant	6/6	3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152106 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74294

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

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

Oct 12, 2021

The c.31G>C (p.D11H) alteration is located in exon 1 (coding exon 1) of the OR2AE1 gene. This alteration results from a G to C substitution at nucleotide position 31, causing the aspartic acid (D) at amino acid position 11 to be replaced by a histidine (H). 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	0.21
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.065
Sift	Benign	0.042	D
Sift4G	Uncertain	0.025	D
Polyphen		1.0	D
Vest4		0.25
MutPred		0.60		Loss of stability (P = 0.064);
MVP		0.32
MPC		0.29
ClinPred		0.94	D
GERP RS		1.7
Varity_R		0.17
gMVP		0.28

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: rs1818642190; hg19: chr7-99474626;