17-247138-G-C

Variant names:

• chr17-247138-G-C
• rs371456304
• NM_006987.4:c.586C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006987.4(RPH3AL):​c.586C>G​(p.Arg196Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPH3AL NM_006987.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPH3AL	NM_006987.4	c.586C>G	p.Arg196Gly	missense_variant	Exon 7 of 10	ENST00000331302.12	NP_008918.1
RPH3AL	NM_001190411.2	c.586C>G	p.Arg196Gly	missense_variant	Exon 6 of 9		NP_001177340.1
RPH3AL	NM_001190412.2	c.499C>G	p.Arg167Gly	missense_variant	Exon 6 of 9		NP_001177341.1
RPH3AL	NM_001190413.2	c.499C>G	p.Arg167Gly	missense_variant	Exon 5 of 8		NP_001177342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPH3AL	ENST00000331302.12	c.586C>G	p.Arg196Gly	missense_variant	Exon 7 of 10	2	NM_006987.4	ENSP00000328977.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251202 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135786

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.586C>G (p.R196G) alteration is located in exon 7 (coding exon 5) of the RPH3AL gene. This alteration results from a C to G substitution at nucleotide position 586, causing the arginine (R) at amino acid position 196 to be replaced by a glycine (G). 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	0.13
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.;.;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.82	T;.;.;T;T
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.68	D;D;D;D;D
MetaSVM	Uncertain	0.00090	D
MutationAssessor	Uncertain	2.2	M;M;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	.;.;.;N;.
REVEL	Benign	0.26
Sift	Uncertain	0.0010	.;.;.;D;.
Sift4G	Uncertain	0.0090	D;D;D;D;.
Polyphen		0.97	D;D;D;D;.
Vest4		0.68
MutPred		0.39		Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);.;.;Loss of MoRF binding (P = 0.0329);
MVP		0.59
MPC		0.33
ClinPred		0.95	D
GERP RS		5.1
Varity_R		0.29
gMVP		0.35

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

Other links and lift over

dbSNP: rs371456304; hg19: chr17-96929;