Genetic Variant NM_006012.4:c.-5G>A (chr19-6361570-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006012.4(CLPP):c.-5G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,398,188 control chromosomes in the GnomAD database, including 914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.051 ( 417 hom., cov: 33)

Exomes 𝑓: 0.020 ( 497 hom. )

Consequence

CLPP
NM_006012.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0600

Publications

3 publications found

Variant links:

Genes affected

CLPP (HGNC:2084): (caseinolytic mitochondrial matrix peptidase proteolytic subunit) The protein encoded by this gene belongs to the peptidase family S14 and hydrolyzes proteins into small peptides in the presence of ATP and magnesium. The protein is transported into mitochondrial matrix and is associated with the inner mitochondrial membrane. [provided by RefSeq, Jul 2008]

CLPP Gene-Disease associations (from GenCC):

Perrault syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
Perrault syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CLPP links:

ENSG00000269802 (HGNC:):

ENSG00000269802 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 19-6361570-G-A is Benign according to our data. Variant chr19-6361570-G-A is described in ClinVar as Benign. ClinVar VariationId is 226522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006012.4. 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
	CLPP	NM_006012.4	MANE Select	c.-5G>A		5_prime_UTR	Exon 1 of 6	NP_006003.1	Q16740

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CLPP	ENST00000245816.11	TSL:1 MANE Select	c.-5G>A	5_prime_UTR	Exon 1 of 6	ENSP00000245816.3	Q16740
CLPP	ENST00000715787.1		c.-5G>A	5_prime_UTR	Exon 1 of 6	ENSP00000520519.1	Q16740
CLPP	ENST00000926271.1		c.-5G>A	5_prime_UTR	Exon 1 of 5	ENSP00000596330.1

Frequencies

GnomAD3 genomes

AF:

0.0508

AC:

7738

AN:

152200

Hom.:

418

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0266

Gnomad ASJ

AF:

0.0173

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0221

Gnomad FIN

AF:

0.0144

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0184

Gnomad OTH

AF:

0.0473

GnomAD2 exomes

AF:

0.0201

AC:

967

AN:

48062

AF XY:

0.0179

show subpopulations

Gnomad AFR exome

AF:

0.137

Gnomad AMR exome

AF:

0.0175

Gnomad ASJ exome

AF:

0.0229

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0128

Gnomad NFE exome

AF:

0.0151

Gnomad OTH exome

AF:

0.0215

GnomAD4 exome

AF:

0.0202

AC:

25113

AN:

1245872

Hom.:

497

Cov.:

AF XY:

0.0200

AC XY:

12052

AN XY:

601202

show subpopulations

African (AFR)

AF:

0.143

AC:

3448

AN:

24042

American (AMR)

AF:

0.0182

AC:

280

AN:

15394

Ashkenazi Jewish (ASJ)

AF:

0.0188

AC:

324

AN:

17210

East Asian (EAS)

AF:

0.00

AC:

AN:

29242

South Asian (SAS)

AF:

0.0221

AC:

1214

AN:

55010

European-Finnish (FIN)

AF:

0.0146

AC:

648

AN:

44350

Middle Eastern (MID)

AF:

0.0645

AC:

312

AN:

4834

European-Non Finnish (NFE)

AF:

0.0176

AC:

17653

AN:

1004710

Other (OTH)

AF:

0.0242

AC:

1234

AN:

51080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

1129

2258

3387

4516

5645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

782

1564

2346

3128

3910

<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:

0.0508

AC:

7742

AN:

152316

Hom.:

417

Cov.:

AF XY:

0.0501

AC XY:

3731

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.136

AC:

5645

AN:

41564

American (AMR)

AF:

0.0265

AC:

406

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0173

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.0222

AC:

107

AN:

4828

European-Finnish (FIN)

AF:

0.0144

AC:

153

AN:

10622

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0184

AC:

1250

AN:

68026

Other (OTH)

AF:

0.0468

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

373

746

1119

1492

1865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0343

Hom.:

Bravo

AF:

0.0547

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Perrault syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

8.9

(source)

DANN

Benign

0.70

PhyloP100

0.060

PromoterAI

-0.037

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over