17-215655-G-C

Variant names:

• chr17-215655-G-C
• rs201484999
• NM_006987.4:c.875C>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 18/23 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P292L) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07962215).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006987.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPH3AL	NM_006987.4	MANE Select	c.875C>G	p.Pro292Arg	missense splice_region	Exon 9 of 10	NP_008918.1	Q9UNE2-1
	RPH3AL	NM_001190411.2		c.875C>G	p.Pro292Arg	missense splice_region	Exon 8 of 9	NP_001177340.1	Q9UNE2-1
	RPH3AL	NM_001190412.2		c.788C>G	p.Pro263Arg	missense splice_region	Exon 8 of 9	NP_001177341.1	Q9UNE2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPH3AL	ENST00000331302.12	TSL:2 MANE Select	c.875C>G	p.Pro292Arg	missense splice_region	Exon 9 of 10	ENSP00000328977.7	Q9UNE2-1
	RPH3AL	ENST00000323434.12	TSL:1	c.788C>G	p.Pro263Arg	missense splice_region	Exon 8 of 9	ENSP00000319210.8	Q9UNE2-2
	RPH3AL	ENST00000953554.1		c.893C>G	p.Pro298Arg	missense splice_region	Exon 8 of 9	ENSP00000623613.1

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

African (AFR) AF: 0.00 AC: 0 AN: 23122

American (AMR) AF: 0.00 AC: 0 AN: 9178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15012

East Asian (EAS) AF: 0.00 AC: 0 AN: 26652

South Asian (SAS) AF: 0.00 AC: 0 AN: 25938

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3036

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 939858

Other (OTH) AF: 0.00 AC: 0 AN: 45520

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-2.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.044
Sift	Uncertain	0.018	D
Sift4G	Benign	0.075	T
Polyphen		0.49	P
Vest4		0.053
MutPred		0.45		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

Other links and lift over

dbSNP: rs201484999; hg19: chr17-65446;