4-4197593-C-G

Position:

• chr4-4197593-C-G

Variant summary

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

The NM_177998.3(OTOP1):​c.1241G>C​(p.Cys414Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 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.)
• Consequence: OTOP1 NM_177998.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOP1	NM_177998.3	c.1241G>C	p.Cys414Ser	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.1241G>C	p.Cys414Ser	missense_variant	5/6	1	NM_177998.3	ENSP00000296358.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

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

Bravo AF: 0.00000756

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

Jul 09, 2021

The c.1241G>C (p.C414S) alteration is located in exon 5 (coding exon 5) of the OTOP1 gene. This alteration results from a G to C substitution at nucleotide position 1241, causing the cysteine (C) at amino acid position 414 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	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Benign	0.52
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0074	T
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.17
Sift	Benign	0.18	T
Sift4G	Benign	0.40	T
Polyphen		0.036	B
Vest4		0.74
MutPred		0.61		Gain of sheet (P = 0.0827);
MVP		0.17
MPC		0.050
ClinPred		0.75	D
GERP RS		3.9
Varity_R		0.16
gMVP		0.45

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: rs1252896007; hg19: chr4-4199320;