Genetic Variant NM_006987.4:c.875C>A (chr17-215655-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006987.4(RPH3AL):c.875C>A(p.Pro292Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,278,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. P292L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 8.9e-7 ( 0 hom. )

Consequence

RPH3AL
NM_006987.4 missense, splice_region

Scores

Splicing: ADA: 0.00003424

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.24

Publications

0 publications found

Variant links:

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]

RPH3AL links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02530405).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPH3AL	NM_006987.4	MANE Select	c.875C>A	p.Pro292Gln	missense splice_region	Exon 9 of 10	NP_008918.1	Q9UNE2-1
RPH3AL	NM_001190411.2		c.875C>A	p.Pro292Gln	missense splice_region	Exon 8 of 9	NP_001177340.1	Q9UNE2-1
RPH3AL	NM_001190412.2		c.788C>A	p.Pro263Gln	missense splice_region	Exon 8 of 9	NP_001177341.1	Q9UNE2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RPH3AL	ENST00000331302.12	TSL:2 MANE Select	c.875C>A	p.Pro292Gln	missense splice_region	Exon 9 of 10	ENSP00000328977.7	Q9UNE2-1
RPH3AL	ENST00000323434.12	TSL:1	c.788C>A	p.Pro263Gln	missense splice_region	Exon 8 of 9	ENSP00000319210.8	Q9UNE2-2
RPH3AL	ENST00000953554.1		c.893C>A	p.Pro298Gln	missense splice_region	Exon 8 of 9	ENSP00000623613.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000458

AC:

AN:

21842

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000646

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:

8.88e-7

AC:

AN:

1126162

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

533946

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23122

American (AMR)

AF:

0.00

AC:

AN:

9178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15012

East Asian (EAS)

AF:

0.00

AC:

AN:

26652

South Asian (SAS)

AF:

0.00

AC:

AN:

25938

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37846

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3036

European-Non Finnish (NFE)

AF:

0.00000106

AC:

AN:

939858

Other (OTH)

AF:

0.00

AC:

AN:

45520

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68042

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000171

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.64

CADD

Benign

5.8

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.058

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.32

M_CAP

Benign

0.0029

MetaRNN

Benign

0.025

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

-2.2

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.59

REVEL

Benign

0.0080

Sift

Uncertain

0.014

Sift4G

Benign

0.14

Polyphen

0.017

Vest4

0.14

MutPred

0.43

Gain of sheet (P = 0.0043)

MVP

0.13

MPC

0.056

ClinPred

0.022

GERP RS

-6.3

Varity_R

0.071

gMVP

0.13

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000034

dbscSNV1_RF

Benign

0.12

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over