rs2388556

chr10-3149631-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014889.4(PITRM1):c.1861G>A(p.Val621Ile) variant causes a missense change. The variant allele was found at a frequency of 0.165 in 1,566,790 control chromosomes in the GnomAD database, including 22,192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. V621V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (1763 hom., cov: 32)
  • Exomes 𝑓: 0.17 (20429 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.86

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)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022476315).
• BP6: Variant 10-3149631-C-T is Benign according to our data. Variant chr10-3149631-C-T is described in ClinVar as [Benign]. Clinvar id is 1300268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITRM1	NM_014889.4	c.1861G>A	p.Val621Ile	missense_variant	16/27	ENST00000224949.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITRM1	ENST00000224949.9	c.1861G>A	p.Val621Ile	missense_variant	16/27	1	NM_014889.4	P3
PITRM1-AS1	ENST00000598280.5	n.269+5645C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22716 AN: 151922 Hom.: 1762 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0999

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.0488

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.146

GnomAD3 exomes AF: 0.144 AC: 30838 AN: 213836 Hom.: 2496 AF XY: 0.148 AC XY: 17196 AN XY: 116250

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0701

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.0537

Gnomad SAS exome AF: 0.144

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.167 AC: 235926 AN: 1414750 Hom.: 20429 Cov.: 31 AF XY: 0.167 AC XY: 116664 AN XY: 700340

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.0762

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.0559

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.200

Gnomad4 NFE exome AF: 0.177

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.149 AC: 22714 AN: 152040 Hom.: 1763 Cov.: 32 AF XY: 0.149 AC XY: 11055 AN XY: 74310

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0997

Gnomad4 ASJ AF: 0.121

Gnomad4 EAS AF: 0.0485

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.211

Gnomad4 NFE AF: 0.172

Gnomad4 OTH AF: 0.145

Alfa AF: 0.159 Hom.: 4970

Bravo AF: 0.138

TwinsUK AF: 0.174 AC: 647

ALSPAC AF: 0.164 AC: 632

ESP6500AA AF: 0.130 AC: 532

ESP6500EA AF: 0.172 AC: 1444

ExAC AF: 0.143 AC: 17253

Asia WGS AF: 0.0830 AC: 290 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

PITRM1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.013	T;.;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;.;.
MutationTaster	Benign	0.0000057	P;P;P;P
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.76	N;N;N;N
REVEL	Benign	0.085
Sift	Benign	0.18	T;T;T;T
Sift4G	Benign	0.17	T;T;T;D
Polyphen		0.97	D;.;.;.
Vest4		0.14
MPC		0.11
ClinPred		0.017	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.42

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

Other links and lift over

dbSNP: rs2388556; hg19: chr10-3191823; COSMIC: COSV56528731; COSMIC: COSV56528731;