10-3138265-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014889.4(PITRM1):c.2990G>A(p.Ser997Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S997T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0340

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013394088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITRM1	NM_014889.4	c.2990G>A	p.Ser997Asn	missense_variant	26/27	ENST00000224949.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITRM1	ENST00000224949.9	c.2990G>A	p.Ser997Asn	missense_variant	26/27	1	NM_014889.4	P3

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000682 AC: 17 AN: 249188 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135196

Gnomad AFR exome AF: 0.000904

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461466 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727050

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74486

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000762 Hom.: 0

Bravo AF: 0.000242

ESP6500AA AF: 0.000937 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000116 AC: 14

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2021

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 899 of the PITRM1 protein (p.Ser899Asn). This variant is present in population databases (rs372883237, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with PITRM1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	2.6
Dann	Benign	0.73
DEOGEN2	Benign	0.028	T;.;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.93	N;N;N;N
REVEL	Benign	0.024
Sift	Benign	0.40	T;T;T;T
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.12
MVP		0.21
MPC		0.049
ClinPred		0.0057	T
GERP RS		-2.6
Varity_R		0.050
gMVP		0.44

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: rs372883237; hg19: chr10-3180457;