17-74941450-C-G

Variant names:

• chr17-74941450-C-G
• rs529811334
• NM_001272005.2:c.77C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001272005.2(OTOP3):​c.77C>G​(p.Pro26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,441,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P26L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: OTOP3 NM_001272005.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.07
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.096074164).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001272005.2. 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
	OTOP3	NM_001272005.2	MANE Select	c.77C>G	p.Pro26Arg	missense	Exon 2 of 7	NP_001258934.1	Q7RTS5-2
	OTOP3	NM_178233.2		c.131C>G	p.Pro44Arg	missense	Exon 2 of 7	NP_839947.1	Q7RTS5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTOP3	ENST00000328801.6	TSL:2 MANE Select	c.77C>G	p.Pro26Arg	missense	Exon 2 of 7	ENSP00000328090.5	Q7RTS5-2
	OTOP3	ENST00000956756.1		c.44C>G	p.Pro15Arg	missense	Exon 2 of 7	ENSP00000626815.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1441628 Hom.: 0 Cov.: 30 AF XY: 0.00000280 AC XY: 2 AN XY: 715492

African (AFR) AF: 0.00 AC: 0 AN: 33076

American (AMR) AF: 0.00 AC: 0 AN: 42260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24794

East Asian (EAS) AF: 0.00 AC: 0 AN: 39480

South Asian (SAS) AF: 0.00 AC: 0 AN: 82996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1101420

Other (OTH) AF: 0.00 AC: 0 AN: 59428

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0038	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.1
PrimateAI	Benign	0.30	T
REVEL	Benign	0.058
Polyphen		0.36	B
MutPred		0.13		Loss of loop (P = 0.0073)
MVP		0.061
MPC		0.065
ClinPred		0.10	T
GERP RS		-0.094
Varity_R		0.048
gMVP		0.11
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs529811334; hg19: chr17-72937545;