12-112828352-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPH3A NM_001143854.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.55
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, PanelApp Australia
• complex neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• congenital myasthenic syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143854.2. 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
	RPH3A	NM_001143854.2	MANE Select	c.34C>A	p.Arg12Ser	missense	Exon 3 of 22	NP_001137326.1	Q9Y2J0-1
	RPH3A	NM_001347952.2		c.34C>A	p.Arg12Ser	missense	Exon 3 of 22	NP_001334881.1	Q9Y2J0-1
	RPH3A	NM_001347953.1		c.34C>A	p.Arg12Ser	missense	Exon 3 of 22	NP_001334882.1	Q9Y2J0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPH3A	ENST00000389385.9	TSL:1 MANE Select	c.34C>A	p.Arg12Ser	missense	Exon 3 of 22	ENSP00000374036.4	Q9Y2J0-1
	RPH3A	ENST00000551052.5	TSL:1	c.34C>A	p.Arg12Ser	missense	Exon 3 of 21	ENSP00000448297.1	Q9Y2J0-2
	RPH3A	ENST00000415485.7	TSL:5	c.34C>A	p.Arg12Ser	missense	Exon 2 of 21	ENSP00000405357.3	Q9Y2J0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.010	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		3.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.62		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
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs535623413; hg19: chr12-113266157;