chr17-215787-G-T

Variant names:

• chr17-215787-G-T
• rs1179963143
• NM_006987.4:c.743C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006987.4(RPH3AL):​c.743C>A​(p.Ala248Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000869 in 1,150,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 8.7e-7 (0 hom.)
• Consequence: RPH3AL NM_006987.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.18

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053299487).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPH3AL	NM_006987.4	c.743C>A	p.Ala248Asp	missense_variant	Exon 9 of 10	ENST00000331302.12	NP_008918.1
RPH3AL	NM_001190411.2	c.743C>A	p.Ala248Asp	missense_variant	Exon 8 of 9		NP_001177340.1
RPH3AL	NM_001190412.2	c.656C>A	p.Ala219Asp	missense_variant	Exon 8 of 9		NP_001177341.1
RPH3AL	NM_001190413.2	c.656C>A	p.Ala219Asp	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.743C>A	p.Ala248Asp	missense_variant	Exon 9 of 10	2	NM_006987.4	ENSP00000328977.7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 8.69e-7 AC: 1 AN: 1150606 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 547764

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000105

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.86
DEOGEN2	Benign	0.044	T;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.62	T;.;.;T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.053	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;L;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.76	.;N;.;N
REVEL	Benign	0.017
Sift	Uncertain	0.015	.;D;.;D
Sift4G	Benign	0.24	T;T;T;T
Polyphen		0.037	B;B;B;B
Vest4		0.13
MutPred		0.39		Loss of MoRF binding (P = 0.085);Loss of MoRF binding (P = 0.085);.;.;
MVP		0.20
MPC		0.096
ClinPred		0.052	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.17

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: rs1179963143; hg19: chr17-65578;