Genetic Variant PRPH:p.Phe21Phe (chr12-49295263-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_006262.4(PRPH):c.63C>T(p.Phe21Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,611,846 control chromosomes in the GnomAD database, including 306 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 37 hom., cov: 33)

Exomes 𝑓: 0.017 ( 269 hom. )

Consequence

PRPH
NM_006262.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: -0.0570

Publications

7 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 12-49295263-C-T is Benign according to our data. Variant chr12-49295263-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 66720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.057 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0213 (3246/152336) while in subpopulation EAS AF = 0.0253 (131/5180). AF 95% confidence interval is 0.0237. There are 37 homozygotes in GnomAd4. There are 1627 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 3246 AD gene.

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.63C>T	p.Phe21Phe	synonymous	Exon 1 of 9	NP_006253.2
	TROAP-AS1	NR_120449.1		n.2809G>A		non_coding_transcript_exon	Exon 6 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRPH	ENST00000257860.9	TSL:1 MANE Select	c.63C>T	p.Phe21Phe	synonymous	Exon 1 of 9	ENSP00000257860.4	P41219-1
TROAP-AS1	ENST00000553259.1	TSL:2	n.2809G>A		non_coding_transcript_exon	Exon 6 of 8
TROAP-AS1	ENST00000797031.1		n.200G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0211

AC:

3218

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0245

Gnomad AMI

AF:

0.0648

Gnomad AMR

AF:

0.0185

Gnomad ASJ

AF:

0.0423

Gnomad EAS

AF:

0.0254

Gnomad SAS

AF:

0.0188

Gnomad FIN

AF:

0.0431

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0143

Gnomad OTH

AF:

0.0220

GnomAD2 exomes

AF:

0.0226

AC:

5398

AN:

238442

AF XY:

0.0224

show subpopulations

Gnomad AFR exome

AF:

0.0258

Gnomad AMR exome

AF:

0.0248

Gnomad ASJ exome

AF:

0.0303

Gnomad EAS exome

AF:

0.0279

Gnomad FIN exome

AF:

0.0457

Gnomad NFE exome

AF:

0.0157

Gnomad OTH exome

AF:

0.0195

GnomAD4 exome

AF:

0.0173

AC:

25235

AN:

1459510

Hom.:

269

Cov.:

AF XY:

0.0173

AC XY:

12573

AN XY:

725992

show subpopulations

African (AFR)

AF:

0.0275

AC:

920

AN:

33434

American (AMR)

AF:

0.0268

AC:

1199

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.0332

AC:

865

AN:

26082

East Asian (EAS)

AF:

0.0248

AC:

985

AN:

39644

South Asian (SAS)

AF:

0.0221

AC:

1901

AN:

86116

European-Finnish (FIN)

AF:

0.0423

AC:

2192

AN:

51832

Middle Eastern (MID)

AF:

0.0220

AC:

127

AN:

5768

European-Non Finnish (NFE)

AF:

0.0142

AC:

15763

AN:

1111648

Other (OTH)

AF:

0.0213

AC:

1283

AN:

60314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

1611

3222

4833

6444

8055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

652

1304

1956

2608

3260

<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:

0.0213

AC:

3246

AN:

152336

Hom.:

Cov.:

AF XY:

0.0218

AC XY:

1627

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0249

AC:

1036

AN:

41580

American (AMR)

AF:

0.0191

AC:

293

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0423

AC:

147

AN:

3472

East Asian (EAS)

AF:

0.0253

AC:

131

AN:

5180

South Asian (SAS)

AF:

0.0186

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0431

AC:

458

AN:

10630

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0143

AC:

971

AN:

68022

Other (OTH)

AF:

0.0241

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

160

320

479

639

799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0162

Hom.:

Bravo

AF:

0.0212

Asia WGS

AF:

0.0480

AC:

168

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0176

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

PRPH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.95

PhyloP100

-0.057

PromoterAI

-0.040

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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