17-215712-C-T

Variant names:

• chr17-215712-C-T
• rs1204012571
• NM_006987.4:c.818G>A

Variant summary

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

The NM_006987.4(RPH3AL):​c.818G>A​(p.Gly273Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000438 in 1,140,430 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: RPH3AL NM_006987.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.99

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.818G>A	p.Gly273Glu	missense_variant	Exon 9 of 10	ENST00000331302.12	NP_008918.1
RPH3AL	NM_001190411.2	c.818G>A	p.Gly273Glu	missense_variant	Exon 8 of 9		NP_001177340.1
RPH3AL	NM_001190412.2	c.731G>A	p.Gly244Glu	missense_variant	Exon 8 of 9		NP_001177341.1
RPH3AL	NM_001190413.2	c.731G>A	p.Gly244Glu	missense_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.818G>A	p.Gly273Glu	missense_variant	Exon 9 of 10	2	NM_006987.4	ENSP00000328977.7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000438 AC: 5 AN: 1140430 Hom.: 0 Cov.: 31 AF XY: 0.00000553 AC XY: 3 AN XY: 542160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000131

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000256

Gnomad4 NFE exome AF: 0.00000105

Gnomad4 OTH exome AF: 0.0000216

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;.;.
Eigen	Benign	0.037
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.74	T;.;.;T
M_CAP	Benign	0.0076	T
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.1	M;M;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	.;.;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	.;.;D;D
Sift4G	Benign	0.20	T;T;T;T
Polyphen		1.0	D;D;D;D
Vest4		0.22
MutPred		0.76		Loss of glycosylation at T274 (P = 0.0966);Loss of glycosylation at T274 (P = 0.0966);.;.;
MVP		0.53
MPC		0.091
ClinPred		0.86	D
GERP RS		3.8
Varity_R		0.21
gMVP		0.15

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: rs1204012571; hg19: chr17-65503;