dbSNP rs11414: PITRM1:p.Arg1007Ser (chr10-3138124-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.3021A>T(p.Arg1007Ser) variant causes a missense, splice region 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. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. R1007R) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PITRM1
NM_014889.4 missense, splice_region

Scores

Splicing: ADA: 0.002833

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.360

Publications

0 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: Illumina, Labcorp Genetics (formerly Invitae)

PITRM1 links:

ENSG00000278419 (HGNC:):

ENSG00000278419 links:

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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=0.24192175).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014889.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PITRM1	NM_014889.4	MANE Select	c.3021A>T	p.Arg1007Ser	missense splice_region	Exon 27 of 27	NP_055704.2
PITRM1	NM_001242307.2		c.3024A>T	p.Arg1008Ser	missense splice_region	Exon 27 of 27	NP_001229236.1	Q5JRX3-2
PITRM1	NM_001347729.1		c.2997A>T	p.Arg999Ser	missense splice_region	Exon 27 of 27	NP_001334658.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PITRM1	ENST00000224949.9	TSL:1 MANE Select	c.3021A>T	p.Arg1007Ser	missense splice_region	Exon 27 of 27	ENSP00000224949.4	Q5JRX3-1
PITRM1	ENST00000380989.6	TSL:1	c.3024A>T	p.Arg1008Ser	missense splice_region	Exon 27 of 27	ENSP00000370377.2	Q5JRX3-2
PITRM1	ENST00000464395.1	TSL:1	n.2844A>T		splice_region non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453588

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722762

African (AFR)

AF:

0.00

AC:

AN:

33306

American (AMR)

AF:

0.00

AC:

AN:

43826

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25928

East Asian (EAS)

AF:

0.00

AC:

AN:

39522

South Asian (SAS)

AF:

0.00

AC:

AN:

85110

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106972

Other (OTH)

AF:

0.00

AC:

AN:

60130

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.44

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.66

M_CAP

Benign

0.028

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

0.36

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.076

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.053

Polyphen

0.040

Vest4

0.34

MutPred

0.51

Gain of disorder (P = 0.0459)

MVP

0.39

MPC

0.061

ClinPred

0.93

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.45

gMVP

0.58

Mutation Taster

=56/44

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0028

dbscSNV1_RF

Benign

0.17

SpliceAI score (max)

0.070

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over