dbSNP rs58599399: PRPH:p.Asp141Asn (chr12-49295621-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.80

Publications

19 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21736407).

BS2

High AC in GnomAdExome4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRPH	NM_006262.4	MANE Select	c.421G>A	p.Asp141Asn	missense	Exon 1 of 9	NP_006253.2
	TROAP-AS1	NR_120449.1		n.2451C>T		non_coding_transcript_exon	Exon 6 of 8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PRPH	ENST00000257860.9	TSL:1 MANE Select	c.421G>A	p.Asp141Asn	missense	Exon 1 of 9	ENSP00000257860.4
TROAP-AS1	ENST00000553259.1	TSL:2	n.2451C>T		non_coding_transcript_exon	Exon 6 of 8
PRPH	ENST00000451891.4	TSL:5	c.100-18G>A		intron	N/A	ENSP00000408897.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000431

AC:

AN:

1393282

Hom.:

Cov.:

AF XY:

0.00000437

AC XY:

AN XY:

687148

show subpopulations

African (AFR)

AF:

0.0000318

AC:

AN:

31496

American (AMR)

AF:

0.00

AC:

AN:

35600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25064

East Asian (EAS)

AF:

0.00

AC:

AN:

35718

South Asian (SAS)

AF:

0.00

AC:

AN:

79190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5526

European-Non Finnish (NFE)

AF:

0.00000464

AC:

AN:

1077752

Other (OTH)

AF:

0.00

AC:

AN:

57828

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Benign

-0.12

Eigen_PC

Benign

0.067

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.69

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.32

MutationAssessor

Benign

1.4

PhyloP100

4.8

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.090

REVEL

Uncertain

0.30

Sift

Benign

0.23

Sift4G

Benign

0.24

Polyphen

0.025

Vest4

0.11

MutPred

0.52

Gain of MoRF binding (P = 0.0436)

MVP

0.91

MPC

0.55

ClinPred

0.82

GERP RS

4.7

PromoterAI

0.0090

Neutral

(source)

Varity_R

0.17

gMVP

0.19

Mutation Taster

=78/22

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over