4-4197474-G-T

Position:

• chr4-4197474-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_177998.3(OTOP1):​c.1360C>A​(p.Leu454Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OTOP1 NM_177998.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.182

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07645032).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOP1	NM_177998.3	c.1360C>A	p.Leu454Ile	missense_variant	5/6	ENST00000296358.5	NP_819056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOP1	ENST00000296358.5	c.1360C>A	p.Leu454Ile	missense_variant	5/6	1	NM_177998.3	ENSP00000296358.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Dec 18, 2023

The c.1360C>A (p.L454I) alteration is located in exon 5 (coding exon 5) of the OTOP1 gene. This alteration results from a C to A substitution at nucleotide position 1360, causing the leucine (L) at amino acid position 454 to be replaced by an isoleucine (I). 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	0.072
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.9
DANN	Benign	0.84
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.015
Sift	Benign	0.24	T
Sift4G	Benign	0.21	T
Polyphen		0.32	B
Vest4		0.060
MutPred		0.36		Loss of glycosylation at P451 (P = 0.0352);
MVP		0.13
MPC		0.040
ClinPred		0.15	T
GERP RS		1.3
Varity_R		0.041
gMVP		0.14

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-4199201;