chr17-215694-G-A

Variant names:

• chr17-215694-G-A
• rs370194292
• NM_006987.4:c.836C>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.836C>T​(p.Pro279Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000495 in 1,274,586 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: RPH3AL NM_006987.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.254
• Publications: 2 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=0.027298033).

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.836C>T	p.Pro279Leu	missense	Exon 9 of 10	NP_008918.1	Q9UNE2-1
	RPH3AL	NM_001190411.2		c.836C>T	p.Pro279Leu	missense	Exon 8 of 9	NP_001177340.1	Q9UNE2-1
	RPH3AL	NM_001190412.2		c.749C>T	p.Pro250Leu	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.836C>T	p.Pro279Leu	missense	Exon 9 of 10	ENSP00000328977.7	Q9UNE2-1
	RPH3AL	ENST00000323434.12	TSL:1	c.749C>T	p.Pro250Leu	missense	Exon 8 of 9	ENSP00000319210.8	Q9UNE2-2
	RPH3AL	ENST00000953554.1		c.854C>T	p.Pro285Leu	missense	Exon 8 of 9	ENSP00000623613.1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152232 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000948 AC: 2 AN: 21098 AF XY: 0.000102

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: 0.000225

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000509 AC: 571 AN: 1122236 Hom.: 0 Cov.: 31 AF XY: 0.000522 AC XY: 278 AN XY: 532178

African (AFR) AF: 0.000260 AC: 6 AN: 23090

American (AMR) AF: 0.000112 AC: 1 AN: 8896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14916

East Asian (EAS) AF: 0.0000751 AC: 2 AN: 26628

South Asian (SAS) AF: 0.000390 AC: 10 AN: 25636

European-Finnish (FIN) AF: 0.000106 AC: 4 AN: 37902

Middle Eastern (MID) AF: 0.000980 AC: 3 AN: 3060

European-Non Finnish (NFE) AF: 0.000549 AC: 514 AN: 936856

Other (OTH) AF: 0.000685 AC: 31 AN: 45252

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152350 Hom.: 1 Cov.: 34 AF XY: 0.000456 AC XY: 34 AN XY: 74496

African (AFR) AF: 0.000409 AC: 17 AN: 41592

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4824

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: 0.000514 AC: 35 AN: 68038

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000485 Hom.: 0

Bravo AF: 0.000287

ESP6500AA AF: 0.000527 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000873 AC: 5

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	0.071
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.25
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.056
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.031	D
Polyphen		0.0060	B
Vest4		0.14
MVP		0.37
MPC		0.062
ClinPred		0.13	T
GERP RS		1.8
Varity_R		0.044
gMVP		0.16
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs370194292; hg19: chr17-65485; COSMIC: COSV100047472; COSMIC: COSV100047472;