rs3814596

Positions:

• chr10-3165440-A-G
• chr10-3165440-A-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.506T>C​(p.Phe169Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,610,222 control chromosomes in the GnomAD database, including 28,845 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 0.17 (2217 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26628 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.66

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=0.0032638013).
• BP6: Variant 10-3165440-A-G is Benign according to our data. Variant chr10-3165440-A-G is described in ClinVar as [Benign]. Clinvar id is 1600892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PITRM1	NM_014889.4	c.506T>C	p.Phe169Ser	missense_variant	5/27	ENST00000224949.9	NP_055704.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITRM1	ENST00000224949.9	c.506T>C	p.Phe169Ser	missense_variant	5/27	1	NM_014889.4	ENSP00000224949	P3
PITRM1-AS1	ENST00000598280.5	n.460+1155A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25534 AN: 152078 Hom.: 2216 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.0506

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.175

GnomAD3 exomes AF: 0.166 AC: 41123 AN: 247752 Hom.: 3714 AF XY: 0.172 AC XY: 23132 AN XY: 134370

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.0818

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.0550

Gnomad SAS exome AF: 0.182

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.188 AC: 273490 AN: 1458026 Hom.: 26628 Cov.: 31 AF XY: 0.188 AC XY: 136520 AN XY: 725350

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.0880

Gnomad4 ASJ exome AF: 0.202

Gnomad4 EAS exome AF: 0.0563

Gnomad4 SAS exome AF: 0.183

Gnomad4 FIN exome AF: 0.215

Gnomad4 NFE exome AF: 0.197

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.168 AC: 25535 AN: 152196 Hom.: 2217 Cov.: 32 AF XY: 0.166 AC XY: 12373 AN XY: 74398

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.209

Gnomad4 EAS AF: 0.0503

Gnomad4 SAS AF: 0.174

Gnomad4 FIN AF: 0.224

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.174

Alfa AF: 0.180 Hom.: 5425

Bravo AF: 0.156

TwinsUK AF: 0.200 AC: 741

ALSPAC AF: 0.192 AC: 741

ESP6500AA AF: 0.140 AC: 523

ESP6500EA AF: 0.194 AC: 1599

ExAC AF: 0.168 AC: 20283

Asia WGS AF: 0.0990 AC: 347 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

PITRM1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 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	0.32
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T;.;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T;T;T
MetaRNN	Benign	0.0033	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	0.0000038	P;P;P
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.17
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.75	P;P;.
Vest4		0.36
MPC		0.40
ClinPred		0.037	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.79

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: rs3814596; hg19: chr10-3207632; COSMIC: COSV56529367; COSMIC: COSV56529367;