10-3138106-C-T

Variant names:

• chr10-3138106-C-T
• rs10175
• NM_014889.4:c.3039G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014889.4(PITRM1):​c.3039G>A​(p.Lys1013Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,604,876 control chromosomes in the GnomAD database, including 59,929 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5697 hom., cov: 33)
  • Exomes 𝑓: 0.27 (54232 hom.)
• Consequence: PITRM1 NM_014889.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.24
• Publications: 24 publications found

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 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive 30

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina

ENSG00000278419 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 10-3138106-C-T is Benign according to our data. Variant chr10-3138106-C-T is described in ClinVar as [Benign]. Clinvar id is 1600998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITRM1	NM_014889.4	c.3039G>A	p.Lys1013Lys	synonymous_variant	Exon 27 of 27	ENST00000224949.9	NP_055704.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITRM1	ENST00000224949.9	c.3039G>A	p.Lys1013Lys	synonymous_variant	Exon 27 of 27	1	NM_014889.4	ENSP00000224949.4

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41203 AN: 151996 Hom.: 5696 Cov.: 33

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.368

Gnomad AMR AF: 0.314

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.205

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.283

Gnomad OTH AF: 0.288

GnomAD2 exomes AF: 0.274 AC: 65964 AN: 240588 AF XY: 0.272

Gnomad AFR exome AF: 0.236

Gnomad AMR exome AF: 0.304

Gnomad ASJ exome AF: 0.371

Gnomad EAS exome AF: 0.169

Gnomad FIN exome AF: 0.321

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.271 AC: 393251 AN: 1452764 Hom.: 54232 Cov.: 35 AF XY: 0.269 AC XY: 194624 AN XY: 722372

African (AFR) AF: 0.237 AC: 7888 AN: 33332

American (AMR) AF: 0.308 AC: 13562 AN: 44028

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 9476 AN: 25904

East Asian (EAS) AF: 0.169 AC: 6694 AN: 39546

South Asian (SAS) AF: 0.211 AC: 17940 AN: 85078

European-Finnish (FIN) AF: 0.320 AC: 16979 AN: 53060

Middle Eastern (MID) AF: 0.362 AC: 2087 AN: 5760

European-Non Finnish (NFE) AF: 0.273 AC: 301652 AN: 1105968

Other (OTH) AF: 0.282 AC: 16973 AN: 60088

GnomAD4 genome AF: 0.271 AC: 41227 AN: 152112 Hom.: 5697 Cov.: 33 AF XY: 0.271 AC XY: 20179 AN XY: 74354

African (AFR) AF: 0.234 AC: 9699 AN: 41494

American (AMR) AF: 0.315 AC: 4804 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 1263 AN: 3468

East Asian (EAS) AF: 0.172 AC: 887 AN: 5170

South Asian (SAS) AF: 0.204 AC: 984 AN: 4824

European-Finnish (FIN) AF: 0.316 AC: 3342 AN: 10584

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.283 AC: 19217 AN: 67982

Other (OTH) AF: 0.287 AC: 606 AN: 2112

Alfa AF: 0.281 Hom.: 10863

Bravo AF: 0.272

Asia WGS AF: 0.186 AC: 647 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PITRM1-related disorder Benign:1

Oct 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.4
DANN	Benign	0.76
PhyloP100		2.2
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10175; hg19: chr10-3180298; COSMIC: COSV56525195; COSMIC: COSV56525195;