chr17-213896-C-T

Variant names:

• chr17-213896-C-T
• rs758708385
• NM_006987.4:c.904G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006987.4(RPH3AL):​c.904G>A​(p.Ala302Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000893 in 1,613,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: RPH3AL NM_006987.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.104
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.059491962).

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.904G>A	p.Ala302Thr	missense	Exon 10 of 10	NP_008918.1	Q9UNE2-1
	RPH3AL	NM_001190411.2		c.904G>A	p.Ala302Thr	missense	Exon 9 of 9	NP_001177340.1	Q9UNE2-1
	RPH3AL	NM_001190412.2		c.817G>A	p.Ala273Thr	missense	Exon 9 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.904G>A	p.Ala302Thr	missense	Exon 10 of 10	ENSP00000328977.7	Q9UNE2-1
	RPH3AL	ENST00000323434.12	TSL:1	c.817G>A	p.Ala273Thr	missense	Exon 9 of 9	ENSP00000319210.8	Q9UNE2-2
	RPH3AL	ENST00000953554.1		c.922G>A	p.Ala308Thr	missense	Exon 9 of 9	ENSP00000623613.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000684 AC: 17 AN: 248450 AF XY: 0.0000518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000981

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000917 AC: 134 AN: 1461188 Hom.: 0 Cov.: 30 AF XY: 0.0000729 AC XY: 53 AN XY: 726888

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.0000224 AC: 1 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86214

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53250

Middle Eastern (MID) AF: 0.000534 AC: 3 AN: 5614

European-Non Finnish (NFE) AF: 0.000104 AC: 116 AN: 1111876

Other (OTH) AF: 0.0000995 AC: 6 AN: 60300

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152112 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74310

African (AFR) AF: 0.0000482 AC: 2 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15214

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000966 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000989 AC: 12

EpiCase AF: 0.000164

EpiControl AF: 0.000119

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	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.10
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.019
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.28	T
Polyphen		0.0020	B
Vest4		0.060
MVP		0.16
MPC		0.18
ClinPred		0.046	T
GERP RS		-3.8
Varity_R		0.052
gMVP		0.076
Mutation Taster		=99/1	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: rs758708385; hg19: chr17-63687;