17-215655-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_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

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]

ACMG classification

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	UniProt
RPH3AL	NM_006987.4	c.875C>T	p.Pro292Leu	missense_variant, splice_region_variant	9/10	ENST00000331302.12
RPH3AL	NM_001190411.2	c.875C>T	p.Pro292Leu	missense_variant, splice_region_variant	8/9
RPH3AL	NM_001190412.2	c.788C>T	p.Pro263Leu	missense_variant, splice_region_variant	8/9
RPH3AL	NM_001190413.2	c.788C>T	p.Pro263Leu	missense_variant, splice_region_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPH3AL	ENST00000331302.12	c.875C>T	p.Pro292Leu	missense_variant, splice_region_variant	9/10	2	NM_006987.4	P1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152248 Hom.: 0 Cov.: 34

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: 2 AN: 21842 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 9982

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: 88 AN: 1126160 Hom.: 0 Cov.: 31 AF XY: 0.0000843 AC XY: 45 AN XY: 533944

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: 26 AN: 152366 Hom.: 0 Cov.: 34 AF XY: 0.000174 AC XY: 13 AN XY: 74510

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: 0

ESP6500EA AF: 0.000131 AC: 1

ExAC AF: 0.0000341 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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	T
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	N
LIST_S2	Benign	0.40	T;.;.;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.0058	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.42	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	T
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

Other links and lift over

dbSNP: rs201484999; hg19: chr17-65446;