17-219659-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006987.4(RPH3AL):c.691A>G(p.Arg231Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,756 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RPH3AL NM_006987.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.100791335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPH3AL	NM_006987.4	c.691A>G	p.Arg231Gly	missense_variant	8/10	ENST00000331302.12
RPH3AL	NM_001190411.2	c.691A>G	p.Arg231Gly	missense_variant	7/9
RPH3AL	NM_001190412.2	c.604A>G	p.Arg202Gly	missense_variant	7/9
RPH3AL	NM_001190413.2	c.604A>G	p.Arg202Gly	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPH3AL	ENST00000331302.12	c.691A>G	p.Arg231Gly	missense_variant	8/10	2	NM_006987.4	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460756 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726650

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 29

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.691A>G (p.R231G) alteration is located in exon 8 (coding exon 6) of the RPH3AL gene. This alteration results from a A to G substitution at nucleotide position 691, causing the arginine (R) at amino acid position 231 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	13
Dann	Benign	0.90
DEOGEN2	Benign	0.037	T;T;.;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.51	T;.;.;T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.52	T
Sift4G	Benign	0.38	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.23
MutPred		0.43		Loss of MoRF binding (P = 0.0185);Loss of MoRF binding (P = 0.0185);.;.;
MVP		0.29
MPC		0.074
ClinPred		0.11	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-69450;