rs4242746

Positions:

• chr10-3159873-T-C
• chr10-3159873-T-G

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.982A>G​(p.Ile328Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 1,597,334 control chromosomes in the GnomAD database, including 367,165 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 0.65 (32026 hom., cov: 32)
  • Exomes 𝑓: 0.68 (335139 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.299

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=7.5671096E-6).
• BP6: Variant 10-3159873-T-C is Benign according to our data. Variant chr10-3159873-T-C is described in ClinVar as [Benign]. Clinvar id is 1607453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PITRM1	NM_014889.4	c.982A>G	p.Ile328Val	missense_variant	9/27	ENST00000224949.9	NP_055704.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PITRM1	ENST00000224949.9	c.982A>G	p.Ile328Val	missense_variant	9/27	1	NM_014889.4	ENSP00000224949	P3
PITRM1-AS1	ENST00000598280.5	n.270-4222T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98393 AN: 151918 Hom.: 32011 Cov.: 32

Gnomad AFR AF: 0.629

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.564

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.666

Gnomad FIN AF: 0.676

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.647

GnomAD3 exomes AF: 0.638 AC: 150572 AN: 235956 Hom.: 48388 AF XY: 0.643 AC XY: 81785 AN XY: 127242

Gnomad AFR exome AF: 0.627

Gnomad AMR exome AF: 0.534

Gnomad ASJ exome AF: 0.561

Gnomad EAS exome AF: 0.580

Gnomad SAS exome AF: 0.670

Gnomad FIN exome AF: 0.678

Gnomad NFE exome AF: 0.672

Gnomad OTH exome AF: 0.638

GnomAD4 exome AF: 0.679 AC: 981669 AN: 1445296 Hom.: 335139 Cov.: 30 AF XY: 0.678 AC XY: 487073 AN XY: 718210

Gnomad4 AFR exome AF: 0.634

Gnomad4 AMR exome AF: 0.537

Gnomad4 ASJ exome AF: 0.566

Gnomad4 EAS exome AF: 0.592

Gnomad4 SAS exome AF: 0.668

Gnomad4 FIN exome AF: 0.679

Gnomad4 NFE exome AF: 0.695

Gnomad4 OTH exome AF: 0.655

GnomAD4 genome AF: 0.648 AC: 98450 AN: 152038 Hom.: 32026 Cov.: 32 AF XY: 0.644 AC XY: 47882 AN XY: 74304

Gnomad4 AFR AF: 0.628

Gnomad4 AMR AF: 0.570

Gnomad4 ASJ AF: 0.564

Gnomad4 EAS AF: 0.589

Gnomad4 SAS AF: 0.666

Gnomad4 FIN AF: 0.676

Gnomad4 NFE AF: 0.681

Gnomad4 OTH AF: 0.643

Alfa AF: 0.666 Hom.: 87223

Bravo AF: 0.637

TwinsUK AF: 0.698 AC: 2588

ALSPAC AF: 0.711 AC: 2739

ESP6500AA AF: 0.680 AC: 1373

ESP6500EA AF: 0.691 AC: 2964

ExAC AF: 0.630 AC: 75967

Asia WGS AF: 0.599 AC: 2085 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.34
DANN	Benign	0.52
DEOGEN2	Benign	0.0069	T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.24	T;T;T
MetaRNN	Benign	0.0000076	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.57	N;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.11	N;N;N
REVEL	Benign	0.032
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.73	T;T;T
Vest4		0.057
MPC		0.045
ClinPred		0.0019	T
GERP RS		0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4242746; hg19: chr10-3202065; COSMIC: COSV56527479; COSMIC: COSV56527479;