rs1127047

chr10-3166320-G-Achr10-3166320-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014889.4(PITRM1):c.327C>T(p.Thr109=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,608,096 control chromosomes in the GnomAD database, including 1,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (239 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1273 hom.)
• Consequence: PITRM1 NM_014889.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.55

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-3166320-G-A is Benign according to our data. Variant chr10-3166320-G-A is described in ClinVar as [Benign]. Clinvar id is 1546017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.55 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITRM1	NM_014889.4	c.327C>T	p.Thr109=	synonymous_variant	4/27	ENST00000224949.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITRM1	ENST00000224949.9	c.327C>T	p.Thr109=	synonymous_variant	4/27	1	NM_014889.4	P3
PITRM1-AS1	ENST00000598280.5	n.461-1512G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7441 AN: 149566 Hom.: 241 Cov.: 33

Gnomad AFR AF: 0.0740

Gnomad AMI AF: 0.0525

Gnomad AMR AF: 0.0666

Gnomad ASJ AF: 0.0316

Gnomad EAS AF: 0.0232

Gnomad SAS AF: 0.0424

Gnomad FIN AF: 0.0421

Gnomad MID AF: 0.0584

Gnomad NFE AF: 0.0356

Gnomad OTH AF: 0.0584

GnomAD3 exomes AF: 0.0469 AC: 11549 AN: 246376 Hom.: 363 AF XY: 0.0446 AC XY: 5971 AN XY: 133748

Gnomad AFR exome AF: 0.0740

Gnomad AMR exome AF: 0.0912

Gnomad ASJ exome AF: 0.0355

Gnomad EAS exome AF: 0.0232

Gnomad SAS exome AF: 0.0481

Gnomad FIN exome AF: 0.0418

Gnomad NFE exome AF: 0.0354

Gnomad OTH exome AF: 0.0410

GnomAD4 exome AF: 0.0386 AC: 56266 AN: 1458406 Hom.: 1273 Cov.: 31 AF XY: 0.0384 AC XY: 27876 AN XY: 725612

Gnomad4 AFR exome AF: 0.0775

Gnomad4 AMR exome AF: 0.0865

Gnomad4 ASJ exome AF: 0.0342

Gnomad4 EAS exome AF: 0.0217

Gnomad4 SAS exome AF: 0.0481

Gnomad4 FIN exome AF: 0.0413

Gnomad4 NFE exome AF: 0.0351

Gnomad4 OTH exome AF: 0.0422

GnomAD4 genome AF: 0.0498 AC: 7453 AN: 149690 Hom.: 239 Cov.: 33 AF XY: 0.0502 AC XY: 3663 AN XY: 73034

Gnomad4 AFR AF: 0.0740

Gnomad4 AMR AF: 0.0668

Gnomad4 ASJ AF: 0.0316

Gnomad4 EAS AF: 0.0233

Gnomad4 SAS AF: 0.0425

Gnomad4 FIN AF: 0.0421

Gnomad4 NFE AF: 0.0356

Gnomad4 OTH AF: 0.0592

Alfa AF: 0.0418 Hom.: 169

Bravo AF: 0.0539

Asia WGS AF: 0.0410 AC: 142 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PITRM1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.066
Dann	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1127047; hg19: chr10-3208512; COSMIC: COSV99828333; COSMIC: COSV99828333;