GeneBe

chr7-108514854-GAATT-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001256007.3(PNPLA8):​c.634_637delAATT​(p.Asn212HisfsTer29) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000248 in 1,610,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PNPLA8
NM_001256007.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.68

Publications

3 publications found
Variant links:
Genes affected
PNPLA8 (HGNC:28900): (patatin like phospholipase domain containing 8) This gene encodes a member of the patatin-like phospholipase domain containing protein family. Members of this family are phospholipases which catalyze the cleavage of fatty acids from membrane phospholipids. The product of this gene is a calcium-independent phospholipase. Mutations in this gene have been associated with mitochondrial myopathy with lactic acidosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2015]
PNPLA8 Gene-Disease associations (from GenCC):
  • mitochondrial myopathy-lactic acidosis-deafness syndrome
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-108514854-GAATT-G is Pathogenic according to our data. Variant chr7-108514854-GAATT-G is described in ClinVar as Pathogenic. ClinVar VariationId is 190127.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256007.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
PNPLA8
NM_001256007.3
MANE Select
c.634_637delAATTp.Asn212HisfsTer29
frameshift
Exon 3 of 11NP_001242936.1Q9NP80-1
PNPLA8
NM_001256008.3
c.634_637delAATTp.Asn212HisfsTer29
frameshift
Exon 2 of 10NP_001242937.1Q9NP80-1
PNPLA8
NM_015723.5
c.634_637delAATTp.Asn212HisfsTer29
frameshift
Exon 4 of 12NP_056538.1Q9NP80-1

Ensembl Transcripts

Sel.
GeneTranscriptTagsHGVScHGVSpEffectExon RankProteinUniProt
PNPLA8
ENST00000257694.13
TSL:1 MANE Select
c.634_637delAATTp.Asn212HisfsTer29
frameshift
Exon 3 of 11ENSP00000257694.8Q9NP80-1
PNPLA8
ENST00000422087.5
TSL:1
c.634_637delAATTp.Asn212HisfsTer29
frameshift
Exon 4 of 12ENSP00000410804.1Q9NP80-1
PNPLA8
ENST00000436062.5
TSL:1
c.634_637delAATTp.Asn212HisfsTer29
frameshift
Exon 2 of 10ENSP00000406779.1Q9NP80-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1457976
Hom.:
0
AF XY:
0.00000138
AC XY:
1
AN XY:
725616
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0000900
AC:
3
AN:
33330
American (AMR)
AF:
0.00
AC:
0
AN:
44516
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26086
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39672
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86014
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53328
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5754
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1109028
Other (OTH)
AF:
0.00
AC:
0
AN:
60248
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.392
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000657
AC:
1
AN:
152146
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74326
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41438
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10594
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68022
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

ClinVar submissions
Significance:Pathogenic
Revision:criteria provided, single submitter
View on ClinVar
Pathogenic
VUS
Benign
Condition
1
-
-
Mitochondrial myopathy-lactic acidosis-deafness syndrome (1)
1
-
-
not provided (1)

Computational scores

Source: dbNSFP v4.9

Name
Calibrated prediction
Score
Prediction
PhyloP100
6.7
Mutation Taster
=0/200
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786205882; hg19: chr7-108155298; API