22-31619745-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001326411.2(PISD):ā€‹c.1097G>Cā€‹(p.Arg366Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R366H) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.000039 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000055 ( 0 hom. )

Consequence

PISD
NM_001326411.2 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.07
Variant links:
Genes affected
PISD (HGNC:8999): (phosphatidylserine decarboxylase) The protein encoded by this gene catalyzes the conversion of phosphatidylserine to phosphatidylethanolamine in the inner mitochondrial membrane. The encoded protein is active in phospholipid metabolism and interorganelle trafficking of phosphatidylserine. [provided by RefSeq, May 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.2193141).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PISDNM_001326411.2 linkuse as main transcriptc.1097G>C p.Arg366Pro missense_variant 8/8 ENST00000439502.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PISDENST00000439502.7 linkuse as main transcriptc.1097G>C p.Arg366Pro missense_variant 8/81 NM_001326411.2 Q9UG56-3

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152228
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
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
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251226
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135848
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461838
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000112
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152346
Hom.:
0
Cov.:
33
AF XY:
0.0000671
AC XY:
5
AN XY:
74494
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000907
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 26, 2024The c.995G>C (p.R332P) alteration is located in exon 9 (coding exon 7) of the PISD gene. This alteration results from a G to C substitution at nucleotide position 995, causing the arginine (R) at amino acid position 332 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 26, 2022This sequence change replaces arginine with proline at codon 366 of the PISD protein (p.Arg366Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs567105342, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PISD-related conditions. ClinVar contains an entry for this variant (Variation ID: 1427703). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.58
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
0.020
CADD
Uncertain
26
DANN
Uncertain
0.99
DEOGEN2
Benign
0.29
.;.;T
Eigen
Benign
0.074
Eigen_PC
Benign
0.11
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.90
.;D;D
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.22
T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
1.9
.;.;L
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.9
N;N;N
REVEL
Benign
0.17
Sift
Benign
0.18
T;T;D
Sift4G
Benign
0.27
T;T;T
Polyphen
0.0050
B;B;P
Vest4
0.57
MutPred
0.57
.;.;Gain of glycosylation at K367 (P = 0.0798);
MVP
0.25
MPC
0.44
ClinPred
0.40
T
GERP RS
3.1
Varity_R
0.48
gMVP
0.86

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs567105342; hg19: chr22-32015731; API