dbSNP rs6901: PITRM1:p.Gln1037Leu (chr10-3138035-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014889.4(PITRM1):c.3110A>T(p.Gln1037Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1037R) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PITRM1
NM_014889.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.939

Publications

42 publications found

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 Gene-Disease associations (from GenCC):

spinocerebellar ataxia, autosomal recessive 30
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina

PITRM1 links:

ENSG00000278419 (HGNC:):

ENSG00000278419 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09636733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITRM1	NM_014889.4 link	c.3110A>T	p.Gln1037Leu	missense_variant	Exon 27 of 27	ENST00000224949.9	NP_055704.2	Q5JRX3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITRM1	ENST00000224949.9 link	c.3110A>T	p.Gln1037Leu	missense_variant	Exon 27 of 27	1	NM_014889.4	ENSP00000224949.4		Q5JRX3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.92e-7

AC:

AN:

1444304

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717774

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33144

American (AMR)

AF:

0.00

AC:

AN:

43264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25772

East Asian (EAS)

AF:

0.00

AC:

AN:

39280

South Asian (SAS)

AF:

0.00

AC:

AN:

83814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5690

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1101042

Other (OTH)

AF:

0.00

AC:

AN:

59802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.024

T;.;.;T

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.66

T;T;T;T

M_CAP

Benign

0.044

MetaRNN

Benign

0.096

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.55

N;.;.;.

PhyloP100

0.94

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.13

N;N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0090

D;D;D;D

Sift4G

Uncertain

0.017

D;D;D;D

Vest4

0.14

MutPred

0.43

.;Gain of stability (P = 0.0061);.;.;

MVP

0.12

MPC

0.050

ClinPred

0.69

GERP RS

0.73

Varity_R

0.11

gMVP

0.60

Mutation Taster

=88/12

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over