Genetic Variant PRPH:p.Arg9Gln (chr12-49295226-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006262.4(PRPH):c.26G>A(p.Arg9Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,611,522 control chromosomes in the GnomAD database, including 254 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 19 hom., cov: 33)

Exomes 𝑓: 0.012 ( 235 hom. )

Consequence

PRPH
NM_006262.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 2.82

Publications

13 publications found

Variant links:

Genes affected

PRPH (HGNC:9461): (peripherin) This gene encodes a cytoskeletal protein found in neurons of the peripheral nervous system. The encoded protein is a type III intermediate filament protein with homology to other cytoskeletal proteins such as desmin, and is a different protein that the peripherin found in photoreceptors. Mutations in this gene have been associated with susceptibility to amyotrophic lateral sclerosis. [provided by RefSeq, Jul 2008]

PRPH links:

TROAP-AS1 (HGNC:55453): (TROAP and PRPH antisense RNA 1)

TROAP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024718642).

BP6

Variant 12-49295226-G-A is Benign according to our data. Variant chr12-49295226-G-A is described in ClinVar as Benign. ClinVar VariationId is 66714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0532 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006262.4. 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
	PRPH	NM_006262.4	MANE Select	c.26G>A	p.Arg9Gln	missense	Exon 1 of 9	NP_006253.2
	TROAP-AS1	NR_120449.1		n.2812+34C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRPH	ENST00000257860.9	TSL:1 MANE Select	c.26G>A	p.Arg9Gln	missense	Exon 1 of 9	ENSP00000257860.4	P41219-1
TROAP-AS1	ENST00000553259.1	TSL:2	n.2812+34C>T		intron	N/A
TROAP-AS1	ENST00000797029.1		n.269-6863C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1533

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0110

Gnomad ASJ

AF:

0.0147

Gnomad EAS

AF:

0.0193

Gnomad SAS

AF:

0.0303

Gnomad FIN

AF:

0.0111

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0117

Gnomad OTH

AF:

0.0220

GnomAD2 exomes

AF:

0.0146

AC:

3456

AN:

236798

AF XY:

0.0161

show subpopulations

Gnomad AFR exome

AF:

0.00220

Gnomad AMR exome

AF:

0.00863

Gnomad ASJ exome

AF:

0.0163

Gnomad EAS exome

AF:

0.0177

Gnomad FIN exome

AF:

0.0115

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.0202

GnomAD4 exome

AF:

0.0120

AC:

17536

AN:

1459214

Hom.:

235

Cov.:

AF XY:

0.0130

AC XY:

9430

AN XY:

725872

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

33430

American (AMR)

AF:

0.00897

AC:

401

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0154

AC:

402

AN:

26082

East Asian (EAS)

AF:

0.0148

AC:

588

AN:

39612

South Asian (SAS)

AF:

0.0330

AC:

2844

AN:

86112

European-Finnish (FIN)

AF:

0.0121

AC:

626

AN:

51728

Middle Eastern (MID)

AF:

0.0583

AC:

336

AN:

5764

European-Non Finnish (NFE)

AF:

0.0102

AC:

11302

AN:

1111530

Other (OTH)

AF:

0.0159

AC:

959

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1158

2315

3473

4630

5788

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

422

844

1266

1688

2110

<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:

0.0101

AC:

1541

AN:

152308

Hom.:

Cov.:

AF XY:

0.00999

AC XY:

744

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00217

AC:

AN:

41570

American (AMR)

AF:

0.0110

AC:

168

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

AN:

3472

East Asian (EAS)

AF:

0.0193

AC:

100

AN:

5182

South Asian (SAS)

AF:

0.0305

AC:

147

AN:

4820

European-Finnish (FIN)

AF:

0.0111

AC:

118

AN:

10630

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0117

AC:

796

AN:

68002

Other (OTH)

AF:

0.0250

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

168

253

337

421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0120

Hom.:

Bravo

AF:

0.00930

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0109

AC:

ESP6500AA

AF:

0.00342

AC:

ESP6500EA

AF:

0.0115

AC:

ExAC

AF:

0.0144

AC:

1741

Asia WGS

AF:

0.0300

AC:

104

AN:

3478

EpiCase

AF:

0.0146

EpiControl

AF:

0.0163

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Amyotrophic lateral sclerosis type 1 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0025

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.8

PhyloP100

2.8

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.32

REVEL

Benign

0.21

Sift

Uncertain

0.0060

Sift4G

Benign

0.14

Polyphen

0.56

Vest4

0.077

MPC

0.70

ClinPred

0.019

GERP RS

3.7

PromoterAI

0.014

Neutral

(source)

Varity_R

0.12

gMVP

0.48

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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