17-215655-G-A

Position:

chr17-215655-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_006987.4(RPH3AL):c.875C>T(p.Pro292Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000892 in 1,278,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

RPH3AL
NM_006987.4 missense, splice_region

Scores

Splicing: ADA: 0.0002630

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.24

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 Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0057888925).

BP6

Variant 17-215655-G-A is Benign according to our data. Variant chr17-215655-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3156012.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
RPH3AL	NM_006987.4 linkuse as main transcript	c.875C>T	p.Pro292Leu	missense_variant, splice_region_variant	9/10	ENST00000331302.12	NP_008918.1
RPH3AL	NM_001190411.2 linkuse as main transcript	c.875C>T	p.Pro292Leu	missense_variant, splice_region_variant	8/9		NP_001177340.1
RPH3AL	NM_001190412.2 linkuse as main transcript	c.788C>T	p.Pro263Leu	missense_variant, splice_region_variant	8/9		NP_001177341.1
RPH3AL	NM_001190413.2 linkuse as main transcript	c.788C>T	p.Pro263Leu	missense_variant, splice_region_variant	7/8		NP_001177342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPH3AL	ENST00000331302.12 linkuse as main transcript	c.875C>T	p.Pro292Leu	missense_variant, splice_region_variant	9/10	2	NM_006987.4	ENSP00000328977	P1	Q9UNE2-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000916

AC:

AN:

21842

Hom.:

AF XY:

0.00

AC XY:

AN XY:

9982

show subpopulations

Gnomad AFR exome

AF:

0.000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00188

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000781

AC:

AN:

1126160

Hom.:

Cov.:

AF XY:

0.0000843

AC XY:

AN XY:

533944

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.000109

Gnomad4 ASJ exome

AF:

0.0000666

Gnomad4 EAS exome

AF:

0.000713

Gnomad4 SAS exome

AF:

0.000347

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000436

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000171

AC:

AN:

152366

Hom.:

Cov.:

AF XY:

0.000174

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000982

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000131

AC:

ExAC

AF:

0.0000341

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 14, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.72

CADD

Benign

5.7

DANN

Benign

0.95

DEOGEN2

Benign

0.11

T;T;.;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.40

T;.;.;T

M_CAP

Benign

0.0020

MetaRNN

Benign

0.0058

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.96

.;.;.;N

REVEL

Benign

0.0020

Sift

Benign

0.29

.;.;.;T

Sift4G

Uncertain

0.046

D;D;T;T

Polyphen

0.0020

B;B;B;B

Vest4

0.058

MVP

0.24

MPC

0.060

ClinPred

0.055

GERP RS

-6.3

Varity_R

0.034

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00026

dbscSNV1_RF

Benign

0.070

SpliceAI score (max)

0.030

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