chr17-215712-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G273V) has been classified as Uncertain significance.

• 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
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.818G>A	p.Gly273Glu	missense	Exon 9 of 10	NP_008918.1	Q9UNE2-1
	RPH3AL	NM_001190411.2		c.818G>A	p.Gly273Glu	missense	Exon 8 of 9	NP_001177340.1	Q9UNE2-1
	RPH3AL	NM_001190412.2		c.731G>A	p.Gly244Glu	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.818G>A	p.Gly273Glu	missense	Exon 9 of 10	ENSP00000328977.7	Q9UNE2-1
	RPH3AL	ENST00000323434.12	TSL:1	c.731G>A	p.Gly244Glu	missense	Exon 8 of 9	ENSP00000319210.8	Q9UNE2-2
	RPH3AL	ENST00000953554.1		c.836G>A	p.Gly279Glu	missense	Exon 8 of 9	ENSP00000623613.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00 AC: 0 AN: 22366 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: 0.00

Gnomad OTH exome AF: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 23200

American (AMR) AF: 0.00 AC: 0 AN: 9270

Ashkenazi Jewish (ASJ) AF: 0.000131 AC: 2 AN: 15320

East Asian (EAS) AF: 0.00 AC: 0 AN: 26722

South Asian (SAS) AF: 0.00 AC: 0 AN: 29424

European-Finnish (FIN) AF: 0.0000256 AC: 1 AN: 39118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3130

European-Non Finnish (NFE) AF: 0.00000105 AC: 1 AN: 948048

Other (OTH) AF: 0.0000216 AC: 1 AN: 46198

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.037
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0076	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.22
MutPred		0.76		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
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1204012571; hg19: chr17-65503;