Genetic Variant RPH3A:p.Thr130Ser (chr12-112866785-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001143854.2(RPH3A):c.389C>G(p.Thr130Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,457,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. T130N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RPH3A
NM_001143854.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.04

Publications

0 publications found

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 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

RPH3A links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18162492).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPH3A	NM_001143854.2	MANE Select	c.389C>G	p.Thr130Ser	missense	Exon 7 of 22	NP_001137326.1	Q9Y2J0-1
RPH3A	NM_001347952.2		c.389C>G	p.Thr130Ser	missense	Exon 7 of 22	NP_001334881.1	Q9Y2J0-1
RPH3A	NM_001347953.1		c.389C>G	p.Thr130Ser	missense	Exon 7 of 22	NP_001334882.1	Q9Y2J0-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPH3A	ENST00000389385.9	TSL:1 MANE Select	c.389C>G	p.Thr130Ser	missense	Exon 7 of 22	ENSP00000374036.4	Q9Y2J0-1
RPH3A	ENST00000551052.5	TSL:1	c.377C>G	p.Thr126Ser	missense	Exon 6 of 21	ENSP00000448297.1	Q9Y2J0-2
RPH3A	ENST00000415485.7	TSL:5	c.389C>G	p.Thr130Ser	missense	Exon 6 of 21	ENSP00000405357.3	Q9Y2J0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1457296

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724508

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39662

South Asian (SAS)

AF:

0.00

AC:

AN:

85608

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53138

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

0.00000541

AC:

AN:

1108944

Other (OTH)

AF:

0.00

AC:

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.23

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.65

M_CAP

Benign

0.0044

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.44

PhyloP100

3.0

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.74

REVEL

Benign

0.11

Sift

Benign

0.17

Sift4G

Benign

0.56

Polyphen

0.0040

Vest4

0.40

MutPred

0.55

Gain of catalytic residue at K125 (P = 6e-04)

MVP

0.38

MPC

0.25

ClinPred

0.39

GERP RS

3.8

Varity_R

0.096

gMVP

0.30

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over