12-49295226-G-A

Position:

chr12-49295226-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000257860.9(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. 12/20 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
ENST00000257860.9 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.82

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:):

TROAP-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 66714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49295226-G-A is described in Lovd as [Likely_benign]. Variant chr12-49295226-G-A is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPH	NM_006262.4 linkuse as main transcript	c.26G>A	p.Arg9Gln	missense_variant	1/9	ENST00000257860.9	NP_006253.2	P41219-1B3KWQ6
TROAP-AS1	NR_120449.1 linkuse as main transcript	n.2812+34C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPH	ENST00000257860.9 linkuse as main transcript	c.26G>A	p.Arg9Gln	missense_variant	1/9	1	NM_006262.4	ENSP00000257860.4		P41219-1
TROAP-AS1	ENST00000553259.1 linkuse as main transcript	n.2812+34C>T		intron_variant		2

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

GnomAD3 exomes

AF:

0.0146

AC:

3456

AN:

236798

Hom.:

AF XY:

0.0161

AC XY:

2094

AN XY:

130034

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 SAS exome

AF:

0.0338

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

Gnomad4 AFR exome

AF:

0.00233

Gnomad4 AMR exome

AF:

0.00897

Gnomad4 ASJ exome

AF:

0.0154

Gnomad4 EAS exome

AF:

0.0148

Gnomad4 SAS exome

AF:

0.0330

Gnomad4 FIN exome

AF:

0.0121

Gnomad4 NFE exome

AF:

0.0102

Gnomad4 OTH exome

AF:

0.0159

GnomAD4 genome

AF:

0.0101

AC:

1541

AN:

152308

Hom.:

Cov.:

AF XY:

0.00999

AC XY:

744

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00217

Gnomad4 AMR

AF:

0.0110

Gnomad4 ASJ

AF:

0.0147

Gnomad4 EAS

AF:

0.0193

Gnomad4 SAS

AF:

0.0305

Gnomad4 FIN

AF:

0.0111

Gnomad4 NFE

AF:

0.0117

Gnomad4 OTH

AF:

0.0250

Alfa

AF:

0.0127

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

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2018	This variant is associated with the following publications: (PMID: 15322088, 25588603, 27884173, 28430856) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	PRPH: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Amyotrophic lateral sclerosis type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 17, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

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

MutationTaster

Benign

0.96

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

Varity_R

0.12

gMVP

0.48

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over