rs3765101

Positions:

• chr10-3155664-C-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.1548G>C​(p.Gln516His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0741 in 1,613,756 control chromosomes in the GnomAD database, including 6,538 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.069 (581 hom., cov: 32)
  • Exomes 𝑓: 0.075 (5957 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.122

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=0.004927784).
• BP6: Variant 10-3155664-C-G is Benign according to our data. Variant chr10-3155664-C-G is described in ClinVar as [Benign]. Clinvar id is 1601727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PITRM1	NM_014889.4	c.1548G>C	p.Gln516His	missense_variant	14/27	ENST00000224949.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PITRM1	ENST00000224949.9	c.1548G>C	p.Gln516His	missense_variant	14/27	1	NM_014889.4	P3
PITRM1-AS1	ENST00000598280.5	n.270-8431C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0690 AC: 10489 AN: 152020 Hom.: 584 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0822

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0608

Gnomad OTH AF: 0.0649

GnomAD3 exomes AF: 0.103 AC: 25720 AN: 249206 Hom.: 1993 AF XY: 0.102 AC XY: 13843 AN XY: 135196

Gnomad AFR exome AF: 0.0320

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.0335

Gnomad EAS exome AF: 0.296

Gnomad SAS exome AF: 0.150

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.0606

Gnomad OTH exome AF: 0.0948

GnomAD4 exome AF: 0.0746 AC: 109036 AN: 1461618 Hom.: 5957 Cov.: 31 AF XY: 0.0762 AC XY: 55373 AN XY: 727096

Gnomad4 AFR exome AF: 0.0260

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.0336

Gnomad4 EAS exome AF: 0.300

Gnomad4 SAS exome AF: 0.144

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.0592

Gnomad4 OTH exome AF: 0.0760

GnomAD4 genome AF: 0.0690 AC: 10495 AN: 152138 Hom.: 581 Cov.: 32 AF XY: 0.0736 AC XY: 5474 AN XY: 74384

Gnomad4 AFR AF: 0.0309

Gnomad4 AMR AF: 0.0822

Gnomad4 ASJ AF: 0.0343

Gnomad4 EAS AF: 0.295

Gnomad4 SAS AF: 0.160

Gnomad4 FIN AF: 0.116

Gnomad4 NFE AF: 0.0607

Gnomad4 OTH AF: 0.0666

Alfa AF: 0.0645 Hom.: 347

Bravo AF: 0.0668

TwinsUK AF: 0.0599 AC: 222

ALSPAC AF: 0.0649 AC: 250

ESP6500AA AF: 0.0302 AC: 125

ESP6500EA AF: 0.0625 AC: 528

ExAC AF: 0.101 AC: 12155

Asia WGS AF: 0.202 AC: 698 AN: 3478

EpiCase AF: 0.0556

EpiControl AF: 0.0561

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	Jan 29, 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	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.4
DANN	Benign	0.74
DEOGEN2	Benign	0.087	T;.;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.55	T;T;T;T
MetaRNN	Benign	0.0049	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M;M;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.4	N;N;D;D
REVEL	Benign	0.11
Sift	Benign	0.11	T;T;D;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.0010	B;B;.;.
Vest4		0.24
MutPred		0.44		Loss of MoRF binding (P = 0.1186);Loss of MoRF binding (P = 0.1186);.;.;
MPC		0.049
ClinPred		0.020	T
GERP RS		-3.1
Varity_R		0.18
gMVP		0.29

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: rs3765101; hg19: chr10-3197856; COSMIC: COSV56528174;