Variant chr17-247138-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006987.4(RPH3AL):c.586C>T(p.Arg196Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000925 in 1,610,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

RPH3AL
NM_006987.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.92

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26128182).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RPH3AL	NM_006987.4 linkuse as main transcript	c.586C>T	p.Arg196Cys	missense_variant	7/10	ENST00000331302.12	NP_008918.1
RPH3AL	NM_001190411.2 linkuse as main transcript	c.586C>T	p.Arg196Cys	missense_variant	6/9		NP_001177340.1
RPH3AL	NM_001190412.2 linkuse as main transcript	c.499C>T	p.Arg167Cys	missense_variant	6/9		NP_001177341.1
RPH3AL	NM_001190413.2 linkuse as main transcript	c.499C>T	p.Arg167Cys	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.586C>T	p.Arg196Cys	missense_variant	7/10	2	NM_006987.4	ENSP00000328977	P1	Q9UNE2-1

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

149612

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000663

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000400

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000744

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251202

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000979

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000910

AC:

133

AN:

1461316

Hom.:

Cov.:

AF XY:

0.0000812

AC XY:

AN XY:

726954

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000883

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000693

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000107

AC:

AN:

149612

Hom.:

Cov.:

AF XY:

0.0000822

AC XY:

AN XY:

73024

show subpopulations

Gnomad4 AFR

AF:

0.000198

Gnomad4 AMR

AF:

0.0000663

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000400

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000744

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000111

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.000123

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.0000593

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

Dec 14, 2022

The c.586C>T (p.R196C) 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 586, causing the arginine (R) at amino acid position 196 to be replaced by a cysteine (C). 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

0.12

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

T;T;.;.;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.91

D;.;.;D;D

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.26

T;T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.2

M;M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-3.0

.;.;.;D;.

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

.;.;.;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D;.

Polyphen

1.0

D;D;D;D;.

Vest4

0.70

MutPred

0.49

Loss of MoRF binding (P = 0.0077);Loss of MoRF binding (P = 0.0077);.;.;Loss of MoRF binding (P = 0.0077);

MVP

0.60

MPC

0.39

ClinPred

0.34

GERP RS

5.1

Varity_R

0.32

gMVP

0.30

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