17-215655-G-C

Variant names:

• chr17-215655-G-C
• NM_006987.4:c.875C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006987.4(RPH3AL):​c.875C>G​(p.Pro292Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000888 in 1,126,162 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: RPH3AL NM_006987.4 missense, splice_region
• Scores: Splicing: ADA: 0.00009629
• Clinical Significance: Not reported in ClinVar
• 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 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=0.07962215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPH3AL	NM_006987.4	c.875C>G	p.Pro292Arg	missense_variant, splice_region_variant	Exon 9 of 10	ENST00000331302.12	NP_008918.1
RPH3AL	NM_001190411.2	c.875C>G	p.Pro292Arg	missense_variant, splice_region_variant	Exon 8 of 9		NP_001177340.1
RPH3AL	NM_001190412.2	c.788C>G	p.Pro263Arg	missense_variant, splice_region_variant	Exon 8 of 9		NP_001177341.1
RPH3AL	NM_001190413.2	c.788C>G	p.Pro263Arg	missense_variant, splice_region_variant	Exon 7 of 8		NP_001177342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPH3AL	ENST00000331302.12	c.875C>G	p.Pro292Arg	missense_variant, splice_region_variant	Exon 9 of 10	2	NM_006987.4	ENSP00000328977.7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 8.88e-7 AC: 1 AN: 1126162 Hom.: 0 Cov.: 31 AF XY: 0.00000187 AC XY: 1 AN XY: 533946

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: 0.00000106

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	5.9
DANN	Benign	0.97
DEOGEN2	Benign	0.067	T;T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.33	T;.;.;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.080	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.96	.;.;.;N
REVEL	Benign	0.044
Sift	Uncertain	0.018	.;.;.;D
Sift4G	Benign	0.075	T;T;T;T
Polyphen		0.49	P;P;P;P
Vest4		0.053
MutPred		0.45		Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);.;.;
MVP		0.19
MPC		0.062
ClinPred		0.27	T
GERP RS		-6.3
Varity_R		0.086
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000096
dbscSNV1_RF	Benign	0.074
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-65446;