rs2388556

Positions:

• 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.

• 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:4
• 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	Protein	UniProt
PITRM1	NM_014889.4	c.1861G>A	p.Val621Ile	missense_variant	16/27	ENST00000224949.9	NP_055704.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITRM1	ENST00000224949.9	c.1861G>A	p.Val621Ile	missense_variant	16/27	1	NM_014889.4	ENSP00000224949	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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

PITRM1-related disorder Benign:1

Benign, no assertion criteria provided

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;