Variant 17-247249-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_006987.4(RPH3AL):c.475C>T(p.Leu159Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,452,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

RPH3AL
NM_006987.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.11

Variant links:

Genes affected

RPH3AL (HGNC:10296): (rabphilin 3A like (without C2 domains)) The protein encoded by this gene plays a direct regulatory role in calcium-ion-dependent exocytosis in both endocrine and exocrine cells and plays a key role in insulin secretion by pancreatic cells. This gene is likely a tumor suppressor. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jun 2010]

RPH3AL 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=0.33108413).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RPH3AL	NM_006987.4 linkuse as main transcript	c.475C>T	p.Leu159Phe	missense_variant	7/10	ENST00000331302.12	NP_008918.1
RPH3AL	NM_001190411.2 linkuse as main transcript	c.475C>T	p.Leu159Phe	missense_variant	6/9		NP_001177340.1
RPH3AL	NM_001190412.2 linkuse as main transcript	c.388C>T	p.Leu130Phe	missense_variant	6/9		NP_001177341.1
RPH3AL	NM_001190413.2 linkuse as main transcript	c.388C>T	p.Leu130Phe	missense_variant	5/8		NP_001177342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPH3AL	ENST00000331302.12 linkuse as main transcript	c.475C>T	p.Leu159Phe	missense_variant	7/10	2	NM_006987.4	ENSP00000328977	P1	Q9UNE2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000408

AC:

AN:

244892

Hom.:

AF XY:

0.00000756

AC XY:

AN XY:

132236

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000905

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1452978

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721712

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000271

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000574

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2023

The c.475C>T (p.L159F) alteration is located in exon 7 (coding exon 5) of the RPH3AL gene. This alteration results from a C to T substitution at nucleotide position 475, causing the leucine (L) at amino acid position 159 to be replaced by a phenylalanine (F). 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

0.21

BayesDel_addAF

Benign

0.0037

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

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

Eigen

Benign

0.16

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.80

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

M_CAP

Benign

0.053

MetaRNN

Benign

0.33

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

MetaSVM

Benign

-0.39

MutationAssessor

Benign

1.9

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

MutationTaster

Benign

0.85

D;N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.9

.;.;.;N;.;.;.

REVEL

Uncertain

0.39

Sift

Benign

0.24

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

Sift4G

Benign

0.42

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

Polyphen

0.10

B;B;D;D;.;.;.

Vest4

0.59

MutPred

0.53

Loss of catalytic residue at L159 (P = 0.0559);Loss of catalytic residue at L159 (P = 0.0559);.;.;Loss of catalytic residue at L159 (P = 0.0559);Loss of catalytic residue at L159 (P = 0.0559);.;

MVP

0.68

MPC

0.32

ClinPred

0.61

GERP RS

4.1

Varity_R

0.14

gMVP

0.17

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