NM_006262.4:c.421G>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_006262.4(PRPH):c.421G>T(p.Asp141Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00542 in 1,545,564 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 0 hom. )

Consequence

PRPH
NM_006262.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2O:2

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0126363635).

BP6

Variant 12-49295621-G-T is Benign according to our data. Variant chr12-49295621-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13707.

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.421G>T	p.Asp141Tyr	missense	Exon 1 of 9	NP_006253.2
	TROAP-AS1	NR_120449.1		n.2451C>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.421G>T	p.Asp141Tyr	missense	Exon 1 of 9	ENSP00000257860.4	P41219-1
PRPH	ENST00000451891.4	TSL:5	c.100-18G>T		intron	N/A	ENSP00000408897.4	F8W835
TROAP-AS1	ENST00000553259.1	TSL:2	n.2451C>A		non_coding_transcript_exon	Exon 6 of 8

Frequencies

GnomAD3 genomes

AF:

0.00360

AC:

548

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00508

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00585

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00321

AC:

451

AN:

140550

AF XY:

0.00292

show subpopulations

Gnomad AFR exome

AF:

0.000761

Gnomad AMR exome

AF:

0.00250

Gnomad ASJ exome

AF:

0.000491

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00421

Gnomad NFE exome

AF:

0.00595

Gnomad OTH exome

AF:

0.00412

GnomAD4 exome

AF:

0.00562

AC:

7830

AN:

1393228

Hom.:

Cov.:

AF XY:

0.00531

AC XY:

3651

AN XY:

687128

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00117

AC:

AN:

31496

American (AMR)

AF:

0.00301

AC:

107

AN:

35598

Ashkenazi Jewish (ASJ)

AF:

0.000439

AC:

AN:

25064

East Asian (EAS)

AF:

0.00

AC:

AN:

35718

South Asian (SAS)

AF:

0.000177

AC:

AN:

79190

European-Finnish (FIN)

AF:

0.00459

AC:

207

AN:

45092

Middle Eastern (MID)

AF:

0.000543

AC:

AN:

5526

European-Non Finnish (NFE)

AF:

0.00669

AC:

7212

AN:

1077716

Other (OTH)

AF:

0.00413

AC:

239

AN:

57828

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.330

Heterozygous variant carriers

806

1612

2418

3224

4030

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

292

584

876

1168

1460

<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:

0.00360

AC:

549

AN:

152336

Hom.:

Cov.:

AF XY:

0.00337

AC XY:

251

AN XY:

74492

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00115

AC:

AN:

41594

American (AMR)

AF:

0.00268

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00508

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00587

AC:

399

AN:

68016

Other (OTH)

AF:

0.00331

AC:

AN:

2114

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.338

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00283

Hom.:

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.000517

AC:

ESP6500EA

AF:

0.00563

AC:

ExAC

AF:

0.00131

AC:

119

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

PRPH-related disorder (1)

Amyotrophic lateral sclerosis, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.65

MetaRNN

Benign

0.013

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

0.075

PhyloP100

4.8

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.8

REVEL

Pathogenic

0.71

Sift

Uncertain

0.014

Sift4G

Uncertain

0.012

Polyphen

0.81

Vest4

0.72

MVP

0.85

MPC

1.5

ClinPred

0.042

GERP RS

4.7

PromoterAI

-0.022

Neutral

(source)

Varity_R

0.24

gMVP

0.40

Mutation Taster

=28/72

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over