chr17-215680-G-A

Variant names:

• chr17-215680-G-A
• rs201204475
• NM_006987.4:c.850C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006987.4(RPH3AL):​c.850C>T​(p.Arg284Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,275,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R284H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: RPH3AL NM_006987.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.17
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022355497).

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.850C>T	p.Arg284Cys	missense	Exon 9 of 10	NP_008918.1	Q9UNE2-1
	RPH3AL	NM_001190411.2		c.850C>T	p.Arg284Cys	missense	Exon 8 of 9	NP_001177340.1	Q9UNE2-1
	RPH3AL	NM_001190412.2		c.763C>T	p.Arg255Cys	missense	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.850C>T	p.Arg284Cys	missense	Exon 9 of 10	ENSP00000328977.7	Q9UNE2-1
	RPH3AL	ENST00000323434.12	TSL:1	c.763C>T	p.Arg255Cys	missense	Exon 8 of 9	ENSP00000319210.8	Q9UNE2-2
	RPH3AL	ENST00000953554.1		c.868C>T	p.Arg290Cys	missense	Exon 8 of 9	ENSP00000623613.1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152236 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000477 AC: 1 AN: 20948 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000112

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000117 AC: 131 AN: 1123430 Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 56 AN XY: 532764

African (AFR) AF: 0.000736 AC: 17 AN: 23094

American (AMR) AF: 0.00 AC: 0 AN: 8978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14950

East Asian (EAS) AF: 0.00 AC: 0 AN: 26632

South Asian (SAS) AF: 0.00 AC: 0 AN: 25748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37910

Middle Eastern (MID) AF: 0.000327 AC: 1 AN: 3058

European-Non Finnish (NFE) AF: 0.000119 AC: 112 AN: 937732

Other (OTH) AF: 0.0000221 AC: 1 AN: 45328

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152354 Hom.: 0 Cov.: 34 AF XY: 0.000268 AC XY: 20 AN XY: 74502

African (AFR) AF: 0.000914 AC: 38 AN: 41596

American (AMR) AF: 0.000196 AC: 3 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000332

ESP6500AA AF: 0.000531 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000350 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.7
DANN	Benign	0.76
DEOGEN2	Benign	0.060	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		-3.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.011
Sift	Benign	0.24	T
Sift4G	Uncertain	0.052	T
Polyphen		0.0	B
Vest4		0.13
MVP		0.27
MPC		0.077
ClinPred		0.051	T
GERP RS		-6.0
Varity_R		0.046
gMVP		0.15
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs201204475; hg19: chr17-65471;