chr12-49295263-C-T

Position:

• chr12-49295263-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The ENST00000257860.9(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 ENST00000257860.9 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.0570

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]

TROAP-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRPH	NM_006262.4	c.63C>T	p.Phe21Phe	synonymous_variant	1/9	ENST00000257860.9	NP_006253.2
TROAP-AS1	NR_120449.1	n.2809G>A		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRPH	ENST00000257860.9	c.63C>T	p.Phe21Phe	synonymous_variant	1/9	1	NM_006262.4	ENSP00000257860.4
TROAP-AS1	ENST00000553259.1	n.2809G>A		non_coding_transcript_exon_variant	6/8	2

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3218 AN: 152218 Hom.: 33 Cov.: 33

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

GnomAD3 exomes AF: 0.0226 AC: 5398 AN: 238442 Hom.: 91 AF XY: 0.0224 AC XY: 2928 AN XY: 130602

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 SAS exome AF: 0.0220

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.: 31 AF XY: 0.0173 AC XY: 12573 AN XY: 725992

Gnomad4 AFR exome AF: 0.0275

Gnomad4 AMR exome AF: 0.0268

Gnomad4 ASJ exome AF: 0.0332

Gnomad4 EAS exome AF: 0.0248

Gnomad4 SAS exome AF: 0.0221

Gnomad4 FIN exome AF: 0.0423

Gnomad4 NFE exome AF: 0.0142

Gnomad4 OTH exome AF: 0.0213

GnomAD4 genome AF: 0.0213 AC: 3246 AN: 152336 Hom.: 37 Cov.: 33 AF XY: 0.0218 AC XY: 1627 AN XY: 74480

Gnomad4 AFR AF: 0.0249

Gnomad4 AMR AF: 0.0191

Gnomad4 ASJ AF: 0.0423

Gnomad4 EAS AF: 0.0253

Gnomad4 SAS AF: 0.0186

Gnomad4 FIN AF: 0.0431

Gnomad4 NFE AF: 0.0143

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.0176 Hom.: 23

Bravo AF: 0.0212

Asia WGS AF: 0.0480 AC: 168 AN: 3478

EpiCase AF: 0.0154

EpiControl AF: 0.0176

ClinVar

Significance: Likely benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2021	- -

PRPH-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.95

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

LitVar

Other links and lift over

dbSNP: rs58403142; hg19: chr12-49689046;