chr17-74941741-C-G

Position:

• chr17-74941741-C-G

Variant summary

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

The NM_001272005.2(OTOP3):​c.368C>G​(p.Ala123Gly) 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. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OTOP3 NM_001272005.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.111

Genes affected

OTOP3 (HGNC:19658): (otopetrin 3) Predicted to enable proton channel activity. Predicted to be involved in proton transmembrane transport. Predicted to be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.13490298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTOP3	NM_001272005.2	c.368C>G	p.Ala123Gly	missense_variant	2/7	ENST00000328801.6	NP_001258934.1
OTOP3	NM_178233.2	c.422C>G	p.Ala141Gly	missense_variant	2/7		NP_839947.1
OTOP3	XM_011524744.3	c.335C>G	p.Ala112Gly	missense_variant	2/7		XP_011523046.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTOP3	ENST00000328801.6	c.368C>G	p.Ala123Gly	missense_variant	2/7	2	NM_001272005.2	ENSP00000328090.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 83

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Oct 01, 2024

The c.422C>G (p.A141G) alteration is located in exon 2 (coding exon 2) of the OTOP3 gene. This alteration results from a C to G substitution at nucleotide position 422, causing the alanine (A) at amino acid position 141 to be replaced by a glycine (G). 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	0.083
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.92
DANN	Benign	0.89
DEOGEN2	Benign	0.016	.;T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.51	T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	.;L
PrimateAI	Benign	0.29	T
REVEL	Benign	0.034
Polyphen		0.56	.;P
MutPred		0.26		.;Loss of helix (P = 0.0626);
MVP		0.088
MPC		0.028
ClinPred		0.16	T
GERP RS		-2.6
Varity_R		0.047
gMVP		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: rs1598604107; hg19: chr17-72937836;