12-49295478-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006262.4(PRPH):​c.278C>T​(p.Thr93Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

PRPH
NM_006262.4 missense

Scores

4
14
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.41
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]
TROAP-AS1 (HGNC:55453): (TROAP and PRPH antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PRPHNM_006262.4 linkc.278C>T p.Thr93Met missense_variant Exon 1 of 9 ENST00000257860.9 NP_006253.2 P41219-1B3KWQ6
TROAP-AS1NR_120449.1 linkn.2594G>A non_coding_transcript_exon_variant Exon 6 of 8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PRPHENST00000257860.9 linkc.278C>T p.Thr93Met missense_variant Exon 1 of 9 1 NM_006262.4 ENSP00000257860.4 P41219-1
PRPHENST00000451891.4 linkc.35C>T p.Thr12Met missense_variant Exon 1 of 6 5 ENSP00000408897.4 F8W835
TROAP-AS1ENST00000553259.1 linkn.2594G>A non_coding_transcript_exon_variant Exon 6 of 8 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 03, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: PRPH c.278C>T (p.Thr93Met) results in a non-conservative amino acid change located in the Intermediate filament head, DNA-binding domain (IPR006821) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. To our knowledge, no occurrence of c.278C>T in individuals affected with Amyotrophic lateral sclerosis type 1 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.50
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D;T
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.085
D
MetaRNN
Uncertain
0.68
D;D
MetaSVM
Uncertain
0.57
D
MutationAssessor
Pathogenic
3.1
M;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Uncertain
-4.0
D;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0080
D;T
Polyphen
1.0
D;.
Vest4
0.23
MutPred
0.55
Loss of glycosylation at T93 (P = 0.0596);.;
MVP
0.86
MPC
1.5
ClinPred
0.99
D
GERP RS
4.6
Varity_R
0.42
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-49689261; API