Variant 12-112828353-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001143854.2(RPH3A):c.35G>T(p.Arg12Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RPH3A
NM_001143854.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.49

Variant links:

Genes affected

RPH3A (HGNC:17056): (rabphilin 3A) The protein encoded by this gene is thought to be an effector for RAB3A, which is a small G protein that acts in the late stages of neurotransmitter exocytosis. The encoded protein may be involved in neurotransmitter release and synaptic vesicle traffic. [provided by RefSeq, Dec 2016]

RPH3A links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPH3A	NM_001143854.2 link	c.35G>T	p.Arg12Leu	missense_variant	3/22	ENST00000389385.9	NP_001137326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPH3A	ENST00000389385.9 link	c.35G>T	p.Arg12Leu	missense_variant	3/22	1	NM_001143854.2	ENSP00000374036.4		Q9Y2J0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455846

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724042

show subpopulations

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2024

The c.35G>T (p.R12L) alteration is located in exon 3 (coding exon 1) of the RPH3A gene. This alteration results from a G to T substitution at nucleotide position 35, causing the arginine (R) at amino acid position 12 to be replaced by a leucine (L). 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

0.20

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

.;T;T;T;T;.;T;T;.;T;T;T;T;T;.;T;.;T

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.93

D;D;D;D;D;.;.;D;D;D;D;D;.;D;D;.;D;D

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.71

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.13

MutationAssessor

Uncertain

2.2

.;.;.;M;.;.;.;.;.;.;.;.;M;.;M;M;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.8

D;D;D;N;D;D;D;D;D;D;D;D;N;D;N;N;D;N

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

D;D;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;T;T;.;D;D;T;T;D;D;T;D;T;T;D;D

Polyphen

1.0, 1.0

.;.;.;D;.;.;.;.;.;.;.;.;D;.;D;D;.;D

Vest4

0.78, 0.78, 0.77, 0.76

MutPred

0.63

Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);Gain of catalytic residue at P16 (P = 0.0055);

MVP

0.87

MPC

1.0

ClinPred

1.0

GERP RS

5.7

Varity_R

0.24

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over