rs1991914

Variant names:

• chr4-4207386-C-A
• rs1991914
• NM_177998.3:c.541-1256G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177998.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOP1	NM_177998.3	MANE Select	c.541-1256G>T		intron	N/A	NP_819056.1	Q7RTM1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOP1	ENST00000296358.5	TSL:1 MANE Select	c.541-1256G>T		intron	N/A	ENSP00000296358.4	Q7RTM1

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

African (AFR) AF: 0.759 AC: 31470 AN: 41476

American (AMR) AF: 0.605 AC: 9236 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.704 AC: 2440 AN: 3468

East Asian (EAS) AF: 0.352 AC: 1822 AN: 5180

South Asian (SAS) AF: 0.701 AC: 3374 AN: 4816

European-Finnish (FIN) AF: 0.591 AC: 6229 AN: 10540

Middle Eastern (MID) AF: 0.648 AC: 188 AN: 290

European-Non Finnish (NFE) AF: 0.669 AC: 45437 AN: 67968

Other (OTH) AF: 0.645 AC: 1364 AN: 2116

Alfa AF: 0.674 Hom.: 18685

Bravo AF: 0.669

Asia WGS AF: 0.534 AC: 1851 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.9
DANN	Benign	0.22
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1991914; hg19: chr4-4209113;