12-112828349-A-G

Position:

• chr12-112828349-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001143854.2(RPH3A):​c.31A>G​(p.Asn11Asp) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPH3A NM_001143854.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08779511).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPH3A	NM_001143854.2	c.31A>G	p.Asn11Asp	missense_variant	3/22	ENST00000389385.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPH3A	ENST00000389385.9	c.31A>G	p.Asn11Asp	missense_variant	3/22	1	NM_001143854.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2023

The c.31A>G (p.N11D) alteration is located in exon 3 (coding exon 1) of the RPH3A gene. This alteration results from a A to G substitution at nucleotide position 31, causing the asparagine (N) at amino acid position 11 to be replaced by an aspartic acid (D). 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	0.064
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.19
DEOGEN2	Benign	0.0025	.;T;T;T;T;.;T;T;.;T;T;T;T;T;.;T;.;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.73	T;T;T;T;T;.;.;T;T;T;T;T;.;T;T;.;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.088	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.47	.;.;.;N;.;.;.;.;.;.;.;.;N;.;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.84	N;N;N;N;N;D;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.026	D;T;T;T;T;.;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T;.;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;B;.;.;.;.;.;.;.;.;B;.;B;B;.;B
Vest4		0.19, 0.19, 0.21, 0.27
MutPred		0.49		Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);Gain of catalytic residue at R12 (P = 0.0013);
MVP		0.55
MPC		0.31
ClinPred		0.12	T
GERP RS		3.4
Varity_R		0.075
gMVP		0.037

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2041915008; hg19: chr12-113266154;