rs58599399

Positions:

• chr12-49295621-G-A
• chr12-49295621-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006262.4(PRPH):​c.421G>A​(p.Asp141Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000431 in 1,393,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D141Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: PRPH NM_006262.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.80

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)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21736407).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRPH	NM_006262.4	c.421G>A	p.Asp141Asn	missense_variant	1/9	ENST00000257860.9
TROAP-AS1	NR_120449.1	n.2451C>T		non_coding_transcript_exon_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRPH	ENST00000257860.9	c.421G>A	p.Asp141Asn	missense_variant	1/9	1	NM_006262.4	P1
TROAP-AS1	ENST00000553259.1	n.2451C>T		non_coding_transcript_exon_variant	6/8	2
PRPH	ENST00000451891.4	c.100-18G>A		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000431 AC: 6 AN: 1393282 Hom.: 0 Cov.: 31 AF XY: 0.00000437 AC XY: 3 AN XY: 687148

Gnomad4 AFR exome AF: 0.0000318

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000464

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.067
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.88	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.090	N
REVEL	Uncertain	0.30
Sift	Benign	0.23	T
Sift4G	Benign	0.24	T
Polyphen		0.025	B
Vest4		0.11
MutPred		0.52		Gain of MoRF binding (P = 0.0436);
MVP		0.91
MPC		0.55
ClinPred		0.82	D
GERP RS		4.7
Varity_R		0.17
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs58599399; hg19: chr12-49689404;