12-112828353-G-T

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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RPH3A
NM_001143854.2 missense

Scores

5
10
4

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]

Genome browser will be placed here

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 UniProt
RPH3ANM_001143854.2 linkuse as main transcriptc.35G>T p.Arg12Leu missense_variant 3/22 ENST00000389385.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPH3AENST00000389385.9 linkuse as main transcriptc.35G>T p.Arg12Leu missense_variant 3/221 NM_001143854.2 P3Q9Y2J0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.87e-7
AC:
1
AN:
1455846
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
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.:
32

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 submitterclinical testingAmbry GeneticsMay 13, 2024The 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
D
BayesDel_noAF
Pathogenic
0.20
CADD
Uncertain
24
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
D
LIST_S2
Uncertain
0.93
D;D;D;D;D;.;.;D;D;D;D;D;.;D;D;.;D;D
M_CAP
Benign
0.043
D
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
D
MutationAssessor
Uncertain
2.2
.;.;.;M;.;.;.;.;.;.;.;.;M;.;M;M;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.53
T
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
D
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.

Other links and lift over

hg19: chr12-113266158; API