12-112828352-C-A

Variant names:

• chr12-112828352-C-A
• rs535623413
• NM_001143854.2:c.34C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001143854.2(RPH3A):​c.34C>A​(p.Arg12Ser) 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 pathogenic 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: RPH3A NM_001143854.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.55

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]

ACMG classification

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, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPH3A	NM_001143854.2	c.34C>A	p.Arg12Ser	missense_variant	Exon 3 of 22	ENST00000389385.9	NP_001137326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPH3A	ENST00000389385.9	c.34C>A	p.Arg12Ser	missense_variant	Exon 3 of 22	1	NM_001143854.2	ENSP00000374036.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.027	.;T;T;T;T;.;T;T;.;T;T;T;T;T;.;T;.;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D;T;T;T;T;.;.;T;T;T;T;T;.;T;T;.;T;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.010	D
MutationAssessor	Uncertain	2.2	.;.;.;M;.;.;.;.;.;.;.;.;M;.;M;M;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.5	D;N;N;N;N;D;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;T;D;D;D;.;D;T;D;D;T;T;D;T;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;T;T;T;.;T;T;T;T;D;D;T;D;T;T;D;D
Polyphen		1.0, 1.0	.;.;.;D;.;.;.;.;.;.;.;.;D;.;D;D;.;D
Vest4		0.72, 0.72, 0.70, 0.72, 0.72
MutPred		0.62		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		0.95
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.24
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs535623413; hg19: chr12-113266157;