Variant chr12-112828361-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001143854.2(RPH3A):c.43T>C(p.Tyr15His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,607,352 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

RPH3A
NM_001143854.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.20

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2711373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPH3A	NM_001143854.2 link	c.43T>C	p.Tyr15His	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.43T>C	p.Tyr15His	missense_variant	3/22	1	NM_001143854.2	ENSP00000374036.4		Q9Y2J0-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000574

AC:

AN:

244056

Hom.:

AF XY:

0.0000681

AC XY:

AN XY:

132110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000307

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000117

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000144

AC:

209

AN:

1455180

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

105

AN XY:

723746

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000228

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:

0.000176

Gnomad4 OTH exome

AF:

0.000216

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000203

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

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

Aug 14, 2024

The c.43T>C (p.Y15H) alteration is located in exon 3 (coding exon 1) of the RPH3A gene. This alteration results from a T to C substitution at nucleotide position 43, causing the tyrosine (Y) at amino acid position 15 to be replaced by a histidine (H). 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

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.052

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

Eigen

Benign

-0.018

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.75

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

M_CAP

Benign

0.028

MetaRNN

Benign

0.27

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.76

MutationAssessor

Benign

1.2

.;.;.;L;.;.;.;.;.;.;.;L;.;L;L;.;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-2.0

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.023

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;T

Sift4G

Benign

0.26

T;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

0.53, 0.47

.;.;.;P;.;.;.;.;.;.;.;P;.;P;P;.;P

Vest4

0.21, 0.21, 0.30

MutPred

0.70

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

0.18

MPC

0.35

ClinPred

0.25

GERP RS

5.7

Varity_R

0.11

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over