rs201388907

Variant names:

• chr17-247200-G-A
• rs201388907
• NM_006987.4:c.524C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006987.4(RPH3AL):​c.524C>T​(p.Pro175Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000377 in 1,614,066 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: RPH3AL NM_006987.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.64

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028376073).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RPH3AL	NM_006987.4	c.524C>T	p.Pro175Leu	missense_variant	Exon 7 of 10	ENST00000331302.12	NP_008918.1
RPH3AL	NM_001190411.2	c.524C>T	p.Pro175Leu	missense_variant	Exon 6 of 9		NP_001177340.1
RPH3AL	NM_001190412.2	c.437C>T	p.Pro146Leu	missense_variant	Exon 6 of 9		NP_001177341.1
RPH3AL	NM_001190413.2	c.437C>T	p.Pro146Leu	missense_variant	Exon 5 of 8		NP_001177342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPH3AL	ENST00000331302.12	c.524C>T	p.Pro175Leu	missense_variant	Exon 7 of 10	2	NM_006987.4	ENSP00000328977.7

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000509 AC: 128 AN: 251240 Hom.: 0 AF XY: 0.000508 AC XY: 69 AN XY: 135794

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.000942

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000358 AC: 524 AN: 1461748 Hom.: 2 Cov.: 31 AF XY: 0.000402 AC XY: 292 AN XY: 727170

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: 0.000693

Gnomad4 NFE exome AF: 0.000409

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000551 AC: 84 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000658 AC XY: 49 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000238

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000601 AC: 73

EpiCase AF: 0.000545

EpiControl AF: 0.000652

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.524C>T (p.P175L) alteration is located in exon 7 (coding exon 5) of the RPH3AL gene. This alteration results from a C to T substitution at nucleotide position 524, causing the proline (P) at amino acid position 175 to be replaced by a leucine (L). 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	0.083
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T;T;.;.;T;T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.74	T;.;.;T;T;T;T
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.028	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;L;.;.;.;.;.
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.6	.;.;.;D;.;.;.
REVEL	Benign	0.25
Sift	Benign	0.18	.;.;.;T;.;.;.
Sift4G	Benign	0.14	T;T;T;T;.;.;.
Polyphen		0.0020	B;B;B;B;.;.;.
Vest4		0.13
MVP		0.54
MPC		0.060
ClinPred		0.023	T
GERP RS		4.1
Varity_R		0.056
gMVP		0.19

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

Publications

LitVar

Other links and lift over

dbSNP: rs201388907; hg19: chr17-96991;