19-9214185-T-G

Variant summary

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

The NM_001005191.3(OR7D4):c.653A>C(p.Tyr218Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000132 in 151,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: OR7D4 NM_001005191.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.55

Genes affected

OR7D4 (HGNC:8380): (olfactory receptor family 7 subfamily D member 4) 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]

OR7E24 (HGNC:):

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, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OR7D4	NM_001005191.3	c.653A>C	p.Tyr218Ser	missense_variant	2/2	ENST00000641669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OR7D4	ENST00000641669.1	c.653A>C	p.Tyr218Ser	missense_variant	2/2		NM_001005191.3	P1
OR7D4	ENST00000308682.3	c.653A>C	p.Tyr218Ser	missense_variant	1/1			P1
OR7D4	ENST00000641244.1	c.653A>C	p.Tyr218Ser	missense_variant	2/2			P1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151924 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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.: 32

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151924 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74210

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

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

Jan 03, 2024

The c.653A>C (p.Y218S) alteration is located in exon 1 (coding exon 1) of the OR7D4 gene. This alteration results from a A to C substitution at nucleotide position 653, causing the tyrosine (Y) at amino acid position 218 to be replaced by a serine (S). 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	0.35
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Benign	0.95
DEOGEN2	Benign	0.015	T;T;T
Eigen	Uncertain	0.48
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.00072	T
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	4.6	H;H;H
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.30	T
Polyphen		1.0	D;D;D
Vest4		0.60
MutPred		0.77		Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);Gain of disorder (P = 0.0081);
MVP		0.77
MPC		0.35
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.84
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1568329317; hg19: chr19-9324861;