10-3138239-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014889.4(PITRM1):c.3016G>C(p.Asp1006His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,612,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

PITRM1
NM_014889.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.240

Publications

3 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09777892).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITRM1	NM_014889.4 link	c.3016G>C	p.Asp1006His	missense_variant	Exon 26 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.3016G>C	p.Asp1006His	missense_variant	Exon 26 of 27	1	NM_014889.4	ENSP00000224949.4		Q5JRX3-1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000309

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000883

AC:

AN:

249114

AF XY:

0.0000962

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000195

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000111

AC:

162

AN:

1459854

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

726394

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86232

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000143

AC:

159

AN:

1110188

Other (OTH)

AF:

0.0000332

AC:

AN:

60328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000138

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000325

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.0000743

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 12, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3019G>C (p.D1007H) alteration is located in exon 26 (coding exon 26) of the PITRM1 gene. This alteration results from a G to C substitution at nucleotide position 3019, causing the aspartic acid (D) at amino acid position 1007 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 908 of the PITRM1 protein (p.Asp908His). This variant is present in population databases (rs758352717, gnomAD 0.02%). 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: 1435139). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

0.069

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.66

CADD

Benign

2.0

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.030

T;.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.49

T;T;T;T

M_CAP

Benign

0.0042

MetaRNN

Benign

0.098

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.44

N;.;.;.

PhyloP100

0.24

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.87

N;N;N;N

REVEL

Benign

0.031

Sift

Benign

0.20

T;T;T;T

Sift4G

Benign

0.10

T;T;T;T

Polyphen

0.0

B;.;.;.

Vest4

0.25

MVP

0.16

MPC

0.058

ClinPred

0.052

GERP RS

-5.4

Varity_R

0.14

gMVP

0.47

Mutation Taster

=82/18

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

10-3138239-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over