10-3143417-C-T

Variant summary

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

The NM_014889.4(PITRM1):​c.2617G>A​(p.Val873Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000374 in 1,612,568 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 (★★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

PITRM1
NM_014889.4 missense

Scores

2
5
12

Clinical Significance

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

Conservation

PhyloP100: 7.46
Variant links:
Genes affected
PITRM1 (HGNC:17663): (pitrilysin metallopeptidase 1) The protein encoded by this gene is an ATP-dependent metalloprotease that degrades post-cleavage mitochondrial transit peptides. The encoded protein binds zinc and can also degrade amyloid beta A4 protein, suggesting a possible role in Alzheimer's disease. [provided by RefSeq, Dec 2016]
PITRM1-AS1 (HGNC:44675): (PITRM1 antisense RNA 1)

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=0.19508696).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PITRM1NM_014889.4 linkc.2617G>A p.Val873Ile missense_variant 23/27 ENST00000224949.9 NP_055704.2 Q5JRX3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PITRM1ENST00000224949.9 linkc.2617G>A p.Val873Ile missense_variant 23/271 NM_014889.4 ENSP00000224949.4 Q5JRX3-1

Frequencies

GnomAD3 genomes
AF:
0.000329
AC:
50
AN:
152176
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000603
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000293
AC:
73
AN:
249154
Hom.:
0
AF XY:
0.000318
AC XY:
43
AN XY:
135172
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.0000869
Gnomad ASJ exome
AF:
0.00109
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000928
Gnomad NFE exome
AF:
0.000478
Gnomad OTH exome
AF:
0.000330
GnomAD4 exome
AF:
0.000379
AC:
553
AN:
1460274
Hom.:
0
Cov.:
30
AF XY:
0.000389
AC XY:
283
AN XY:
726638
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00138
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000375
Gnomad4 NFE exome
AF:
0.000447
Gnomad4 OTH exome
AF:
0.000249
GnomAD4 genome
AF:
0.000328
AC:
50
AN:
152294
Hom.:
0
Cov.:
33
AF XY:
0.000349
AC XY:
26
AN XY:
74462
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.000603
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000460
Hom.:
0
Bravo
AF:
0.000329
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.000248
AC:
1
ESP6500EA
AF:
0.000720
AC:
6
ExAC
AF:
0.000347
AC:
42
EpiCase
AF:
0.000218
EpiControl
AF:
0.000652

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 09, 2024The c.2620G>A (p.V874I) alteration is located in exon 23 (coding exon 23) of the PITRM1 gene. This alteration results from a G to A substitution at nucleotide position 2620, causing the valine (V) at amino acid position 874 to be replaced by an isoleucine (I). 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), LabcorpJan 24, 2024This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 775 of the PITRM1 protein (p.Val775Ile). This variant is present in population databases (rs200737276, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with PITRM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1347980). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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
Benign
0.10
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.45
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.024
T;.;.;T;.
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.83
T;T;T;T;D
M_CAP
Benign
0.013
T
MetaRNN
Benign
0.20
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Pathogenic
3.0
M;.;.;.;.
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.93
N;N;N;N;N
REVEL
Benign
0.21
Sift
Uncertain
0.0050
D;D;D;D;D
Sift4G
Uncertain
0.0090
D;D;D;T;D
Polyphen
0.92
P;.;.;.;.
Vest4
0.30
MVP
0.54
MPC
0.20
ClinPred
0.36
T
GERP RS
5.0
Varity_R
0.25
gMVP
0.52

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: rs200737276; hg19: chr10-3185609; COSMIC: COSV56538604; COSMIC: COSV56538604; API