Genetic Variant PITRM1:p.Gln516His (chr10-3155664-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014889.4(PITRM1):c.1548G>C(p.Gln516His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0741 in 1,613,756 control chromosomes in the GnomAD database, including 6,538 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.069 ( 581 hom., cov: 32)

Exomes 𝑓: 0.075 ( 5957 hom. )

Consequence

PITRM1
NM_014889.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.122

Publications

17 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 links:

PITRM1-AS1 (HGNC:44675): (PITRM1 antisense RNA 1)

PITRM1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004927784).

BP6

Variant 10-3155664-C-G is Benign according to our data. Variant chr10-3155664-C-G is described in ClinVar as Benign. ClinVar VariationId is 1601727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITRM1	NM_014889.4 link	c.1548G>C	p.Gln516His	missense_variant	Exon 14 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.1548G>C	p.Gln516His	missense_variant	Exon 14 of 27	1	NM_014889.4	ENSP00000224949.4		Q5JRX3-1

Frequencies

GnomAD3 genomes

AF:

0.0690

AC:

10489

AN:

152020

Hom.:

584

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0308

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0822

Gnomad ASJ

AF:

0.0343

Gnomad EAS

AF:

0.296

Gnomad SAS

AF:

0.160

Gnomad FIN

AF:

0.116

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0608

Gnomad OTH

AF:

0.0649

GnomAD2 exomes

AF:

0.103

AC:

25720

AN:

249206

AF XY:

0.102

show subpopulations

Gnomad AFR exome

AF:

0.0320

Gnomad AMR exome

AF:

0.148

Gnomad ASJ exome

AF:

0.0335

Gnomad EAS exome

AF:

0.296

Gnomad FIN exome

AF:

0.114

Gnomad NFE exome

AF:

0.0606

Gnomad OTH exome

AF:

0.0948

GnomAD4 exome

AF:

0.0746

AC:

109036

AN:

1461618

Hom.:

5957

Cov.:

AF XY:

0.0762

AC XY:

55373

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.0260

AC:

872

AN:

33478

American (AMR)

AF:

0.141

AC:

6306

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0336

AC:

879

AN:

26136

East Asian (EAS)

AF:

0.300

AC:

11904

AN:

39696

South Asian (SAS)

AF:

0.144

AC:

12429

AN:

86252

European-Finnish (FIN)

AF:

0.113

AC:

6053

AN:

53374

Middle Eastern (MID)

AF:

0.0269

AC:

155

AN:

5766

European-Non Finnish (NFE)

AF:

0.0592

AC:

65847

AN:

1111826

Other (OTH)

AF:

0.0760

AC:

4591

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

4936

9872

14809

19745

24681

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2682

5364

8046

10728

13410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0690

AC:

10495

AN:

152138

Hom.:

581

Cov.:

AF XY:

0.0736

AC XY:

5474

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0309

AC:

1285

AN:

41540

American (AMR)

AF:

0.0822

AC:

1256

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.0343

AC:

119

AN:

3470

East Asian (EAS)

AF:

0.295

AC:

1515

AN:

5130

South Asian (SAS)

AF:

0.160

AC:

771

AN:

4814

European-Finnish (FIN)

AF:

0.116

AC:

1227

AN:

10592

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0607

AC:

4130

AN:

67990

Other (OTH)

AF:

0.0666

AC:

141

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

480

959

1439

1918

2398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

142

284

426

568

710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0645

Hom.:

347

Bravo

AF:

0.0668

TwinsUK

AF:

0.0599

AC:

222

ALSPAC

AF:

0.0649

AC:

250

ESP6500AA

AF:

0.0302

AC:

125

ESP6500EA

AF:

0.0625

AC:

528

ExAC

AF:

0.101

AC:

12155

Asia WGS

AF:

0.202

AC:

698

AN:

3478

EpiCase

AF:

0.0556

EpiControl

AF:

0.0561

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.48

CADD

Benign

5.4

(source)

DANN

Benign

0.74

DEOGEN2

Benign

0.087

T;.;.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.55

T;T;T;T

MetaRNN

Benign

0.0049

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.6

M;M;.;.

PhyloP100

0.12

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.4

N;N;D;D

REVEL

Benign

0.11

Sift

Benign

0.11

T;T;D;T

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.0010

B;B;.;.

Vest4

0.24

MutPred

0.44

Loss of MoRF binding (P = 0.1186);Loss of MoRF binding (P = 0.1186);.;.;

MPC

0.049

ClinPred

0.020

GERP RS

-3.1

Varity_R

0.18

gMVP

0.29

Mutation Taster

=96/4

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over