10-3138096-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014889.4(PITRM1):c.3049G>A(p.Gly1017Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0262 in 1,609,880 control chromosomes in the GnomAD database, including 672 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (40 hom., cov: 34)
  • Exomes 𝑓: 0.027 (632 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.84

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0100236535).
• BP6: Variant 10-3138096-C-T is Benign according to our data. Variant chr10-3138096-C-T is described in ClinVar as [Benign]. Clinvar id is 1628450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0188 (2866/152290) while in subpopulation NFE AF= 0.0307 (2089/68030). AF 95% confidence interval is 0.0296. There are 40 homozygotes in gnomad4. There are 1258 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITRM1	NM_014889.4	c.3049G>A	p.Gly1017Ser	missense_variant	27/27	ENST00000224949.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITRM1	ENST00000224949.9	c.3049G>A	p.Gly1017Ser	missense_variant	27/27	1	NM_014889.4	P3

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2867 AN: 152172 Hom.: 40 Cov.: 34

Gnomad AFR AF: 0.00586

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0180 AC: 4374 AN: 242422 Hom.: 70 AF XY: 0.0184 AC XY: 2417 AN XY: 131342

Gnomad AFR exome AF: 0.00446

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.000226

Gnomad SAS exome AF: 0.00253

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.0304

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0270 AC: 39326 AN: 1457590 Hom.: 632 Cov.: 34 AF XY: 0.0264 AC XY: 19128 AN XY: 724570

Gnomad4 AFR exome AF: 0.00488

Gnomad4 AMR exome AF: 0.0139

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00249

Gnomad4 FIN exome AF: 0.0127

Gnomad4 NFE exome AF: 0.0323

Gnomad4 OTH exome AF: 0.0230

GnomAD4 genome AF: 0.0188 AC: 2866 AN: 152290 Hom.: 40 Cov.: 34 AF XY: 0.0169 AC XY: 1258 AN XY: 74480

Gnomad4 AFR AF: 0.00585

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0133

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0118

Gnomad4 NFE AF: 0.0307

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0268 Hom.: 47

Bravo AF: 0.0191

TwinsUK AF: 0.0353 AC: 131

ALSPAC AF: 0.0309 AC: 119

ESP6500AA AF: 0.00611 AC: 26

ESP6500EA AF: 0.0314 AC: 266

ExAC AF: 0.0176 AC: 2133

Asia WGS AF: 0.00231 AC: 8 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 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). -

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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T;T;T
MetaRNN	Benign	0.010	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Benign	0.20
Sift	Benign	0.051	T;T;T;T
Sift4G	Uncertain	0.056	T;T;T;T
Polyphen		0.99	D;.;.;.
Vest4		0.14
MPC		0.061
ClinPred		0.039	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.77

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: rs35779348; hg19: chr10-3180288;