rs1991914

Positions:

• chr4-4207386-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_177998.3(OTOP1):​c.541-1256G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.671 in 152,042 control chromosomes in the GnomAD database, including 34,845 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.67 (34845 hom., cov: 33)
• Consequence: OTOP1 NM_177998.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.560

Genes affected

OTOP1 (HGNC:19656): (otopetrin 1) This gene encodes a transmembrane protein which belongs to the otopetrin domain protein family and is required for the formation of otoconia and otoliths, calcium carbonate biominerals within the inner ear of mammals that are required for the detection of linear acceleration and gravity. This gene modulates purinergic control of intracellular calcium in vestibular supporting cells. Naturally occurring mutations in the orthologous mouse gene are associated with nonsyndromic otoconia agenesis and a consequent balance defect. The orthologous mouse gene is also induced in white adipose tissue during obesity. The encoded protein is a component of a counterinflammatory pathway that attenuates obesity-induced adipose tissue inflammation and plays an adaptive role in maintaining metabolic homeostasis in obesity. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOP1	NM_177998.3	c.541-1256G>T		intron_variant		ENST00000296358.5	NP_819056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOP1	ENST00000296358.5	c.541-1256G>T		intron_variant		1	NM_177998.3	ENSP00000296358	P1

Frequencies

GnomAD3 genomes AF: 0.671 AC: 101991 AN: 151926 Hom.: 34807 Cov.: 33

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.576

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.704

Gnomad EAS AF: 0.351

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.591

Gnomad MID AF: 0.638

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.644

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.671 AC: 102085 AN: 152042 Hom.: 34845 Cov.: 33 AF XY: 0.664 AC XY: 49364 AN XY: 74306

Gnomad4 AFR AF: 0.759

Gnomad4 AMR AF: 0.605

Gnomad4 ASJ AF: 0.704

Gnomad4 EAS AF: 0.352

Gnomad4 SAS AF: 0.701

Gnomad4 FIN AF: 0.591

Gnomad4 NFE AF: 0.669

Gnomad4 OTH AF: 0.645

Alfa AF: 0.686 Hom.: 11316

Bravo AF: 0.669

Asia WGS AF: 0.534 AC: 1851 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.9
DANN	Benign	0.22

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: rs1991914; hg19: chr4-4209113;