12-49295621-G-T

Position:

chr12-49295621-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_006262.4(PRPH):c.421G>T(p.Asp141Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00542 in 1,545,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 0 hom. )

Consequence

PRPH
NM_006262.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2O:2

Conservation

PhyloP100: 4.80

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 made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0126363635).

BP6

Variant 12-49295621-G-T is Benign according to our data. Variant chr12-49295621-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13707.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Uncertain_significance=3, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPH	NM_006262.4 linkuse as main transcript	c.421G>T	p.Asp141Tyr	missense_variant	1/9	ENST00000257860.9
TROAP-AS1	NR_120449.1 linkuse as main transcript	n.2451C>A		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPH	ENST00000257860.9 linkuse as main transcript	c.421G>T	p.Asp141Tyr	missense_variant	1/9	1	NM_006262.4	P1	P41219-1
TROAP-AS1	ENST00000553259.1 linkuse as main transcript	n.2451C>A		non_coding_transcript_exon_variant	6/8	2
PRPH	ENST00000451891.4 linkuse as main transcript	c.100-18G>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00360

AC:

548

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00508

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00585

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00321

AC:

451

AN:

140550

Hom.:

AF XY:

0.00292

AC XY:

223

AN XY:

76292

show subpopulations

Gnomad AFR exome

AF:

0.000761

Gnomad AMR exome

AF:

0.00250

Gnomad ASJ exome

AF:

0.000491

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000177

Gnomad FIN exome

AF:

0.00421

Gnomad NFE exome

AF:

0.00595

Gnomad OTH exome

AF:

0.00412

GnomAD4 exome

AF:

0.00562

AC:

7830

AN:

1393228

Hom.:

Cov.:

AF XY:

0.00531

AC XY:

3651

AN XY:

687128

show subpopulations

Gnomad4 AFR exome

AF:

0.00117

Gnomad4 AMR exome

AF:

0.00301

Gnomad4 ASJ exome

AF:

0.000439

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000177

Gnomad4 FIN exome

AF:

0.00459

Gnomad4 NFE exome

AF:

0.00669

Gnomad4 OTH exome

AF:

0.00413

GnomAD4 genome

AF:

0.00360

AC:

549

AN:

152336

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00115

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00508

Gnomad4 NFE

AF:

0.00587

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00283

Hom.:

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.000517

AC:

ESP6500EA

AF:

0.00563

AC:

ExAC

AF:

0.00131

AC:

119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2023	Variant summary: PRPH c.421G>T (p.Asp141Tyr) results in a non-conservative amino acid change located in the Intermediate filament, rod domain (IPR039008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 140550 control chromosomes. This frequency does not allow conclusions about variant significance due to lack of accurate figures supporting the prevalence of PRPH-associated Amyotrophic Lateral Sclerosis Type 1 and limited reported association of this gene with the phenotype (Clingen, 2022). Furthermore, low to variable penetrance, role as a susceptibility factor and possibility of pre-symptomatic individuals in the control populations have each been speculated (Gromicho_2020). c.421G>T has been reported in the literature in individuals affected with features of Familial Amyotrophic Lateral Sclerosis (FALS) and in unaffected controls (example, Gromicho_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Amyotrophic Lateral Sclerosis Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32638105). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=2; LB, n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2017	The D141Y variant in the PRPH gene has been reported previously in the homozygous and heterozygous state in unrelated individuals with ALS (Leung et al., 2004; Corrado et al., 2011). The D141Y variant is observed in 373/64280 (0.58%) alleles in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The D141Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret D141Y as a variant of uncertain significance. -

PRPH-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 21, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Amyotrophic lateral sclerosis, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.65

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

0.075

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.8

REVEL

Pathogenic

0.71

Sift

Uncertain

0.014

Sift4G

Uncertain

0.012

Polyphen

0.81

Vest4

0.72

MVP

0.85

MPC

1.5

ClinPred

0.042

GERP RS

4.7

Varity_R

0.24

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

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

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