Genetic Variant RPH3A:p.Thr51Ile (chr12-112847764-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001347955.2(RPH3A):c.-50C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

RPH3A
NM_001347955.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.33

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPH3A	NM_001143854.2 link	c.152C>T	p.Thr51Ile	missense_variant	Exon 5 of 22	ENST00000389385.9	NP_001137326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPH3A	ENST00000389385.9 link	c.152C>T	p.Thr51Ile	missense_variant	Exon 5 of 22	1	NM_001143854.2	ENSP00000374036.4		Q9Y2J0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.78

D;D;D;D;D;D;.;D;D;D;D;D;.;D;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D;D;.;D;D;D;D;D;.;D;D;.;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

2.9

.;.;M;.;.;.;.;.;.;.;M;.;.;M;.

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-4.2

D;D;N;D;D;D;D;D;D;D;N;D;N;N;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0030

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;.;D;.;.;.;.;.;.;.;D;.;D;D;.

Vest4

0.85, 0.86, 0.85

MutPred

0.45

Loss of phosphorylation at T51 (P = 0.0266);Loss of phosphorylation at T51 (P = 0.0266);Loss of phosphorylation at T51 (P = 0.0266);Loss of phosphorylation at T51 (P = 0.0266);Loss of phosphorylation at T51 (P = 0.0266);Loss of phosphorylation at T51 (P = 0.0266);Loss of phosphorylation at T51 (P = 0.0266);Loss of phosphorylation at T51 (P = 0.0266);Loss of phosphorylation at T51 (P = 0.0266);Loss of phosphorylation at T51 (P = 0.0266);Loss of phosphorylation at T51 (P = 0.0266);Loss of phosphorylation at T51 (P = 0.0266);.;Loss of phosphorylation at T51 (P = 0.0266);Loss of phosphorylation at T51 (P = 0.0266);

MVP

0.76

MPC

0.76

ClinPred

1.0

GERP RS

5.1

Varity_R

0.42

gMVP

0.95

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over