NM_014889.4:c.3110A>G

Variant names:

• chr10-3138035-T-C
• rs6901
• NM_014889.4:c.3110A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014889.4(PITRM1):​c.3110A>G​(p.Gln1037Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.712 in 1,593,702 control chromosomes in the GnomAD database, including 404,664 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.70 (37522 hom., cov: 33)
  • Exomes 𝑓: 0.71 (367142 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.939
• Publications: 42 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: Illumina, Labcorp Genetics (formerly Invitae)

ENSG00000278419 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0319361E-6).
• BP6: Variant 10-3138035-T-C is Benign according to our data. Variant chr10-3138035-T-C is described in ClinVar as Benign. ClinVar VariationId is 1598743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.72 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014889.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITRM1	NM_014889.4	MANE Select	c.3110A>G	p.Gln1037Arg	missense	Exon 27 of 27	NP_055704.2
	PITRM1	NM_001242307.2		c.3113A>G	p.Gln1038Arg	missense	Exon 27 of 27	NP_001229236.1	Q5JRX3-2
	PITRM1	NM_001347729.1		c.3086A>G	p.Gln1029Arg	missense	Exon 27 of 27	NP_001334658.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITRM1	ENST00000224949.9	TSL:1 MANE Select	c.3110A>G	p.Gln1037Arg	missense	Exon 27 of 27	ENSP00000224949.4	Q5JRX3-1
	PITRM1	ENST00000380989.6	TSL:1	c.3113A>G	p.Gln1038Arg	missense	Exon 27 of 27	ENSP00000370377.2	Q5JRX3-2
	PITRM1	ENST00000464395.1	TSL:1	n.2933A>G		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes AF: 0.702 AC: 106666 AN: 151958 Hom.: 37495 Cov.: 33

Gnomad AFR AF: 0.710

Gnomad AMI AF: 0.668

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.611

Gnomad EAS AF: 0.740

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.696

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.712

GnomAD2 exomes AF: 0.702 AC: 163342 AN: 232586 AF XY: 0.702

Gnomad AFR exome AF: 0.707

Gnomad AMR exome AF: 0.713

Gnomad ASJ exome AF: 0.612

Gnomad EAS exome AF: 0.738

Gnomad FIN exome AF: 0.688

Gnomad NFE exome AF: 0.701

Gnomad OTH exome AF: 0.687

GnomAD4 exome AF: 0.713 AC: 1027768 AN: 1441626 Hom.: 367142 Cov.: 29 AF XY: 0.712 AC XY: 510074 AN XY: 716474

African (AFR) AF: 0.713 AC: 23567 AN: 33072

American (AMR) AF: 0.707 AC: 30571 AN: 43218

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 15792 AN: 25744

East Asian (EAS) AF: 0.751 AC: 29481 AN: 39254

South Asian (SAS) AF: 0.712 AC: 59657 AN: 83738

European-Finnish (FIN) AF: 0.688 AC: 36094 AN: 52452

Middle Eastern (MID) AF: 0.632 AC: 3591 AN: 5680

European-Non Finnish (NFE) AF: 0.716 AC: 787159 AN: 1098736

Other (OTH) AF: 0.701 AC: 41856 AN: 59732

GnomAD4 genome AF: 0.702 AC: 106738 AN: 152076 Hom.: 37522 Cov.: 33 AF XY: 0.702 AC XY: 52191 AN XY: 74350

African (AFR) AF: 0.709 AC: 29411 AN: 41464

American (AMR) AF: 0.680 AC: 10388 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 2119 AN: 3470

East Asian (EAS) AF: 0.740 AC: 3822 AN: 5168

South Asian (SAS) AF: 0.714 AC: 3442 AN: 4822

European-Finnish (FIN) AF: 0.696 AC: 7352 AN: 10566

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.705 AC: 47925 AN: 67984

Other (OTH) AF: 0.707 AC: 1493 AN: 2112

Alfa AF: 0.702 Hom.: 150394

Bravo AF: 0.703

TwinsUK AF: 0.717 AC: 2658

ALSPAC AF: 0.726 AC: 2799

ESP6500AA AF: 0.723 AC: 2947

ESP6500EA AF: 0.710 AC: 5936

ExAC AF: 0.688 AC: 82842

Asia WGS AF: 0.690 AC: 2399 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.8
DANN	Benign	0.39
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.9	N
PhyloP100		0.94
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.64	N
REVEL	Benign	0.11
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.028
MPC		0.054
ClinPred		0.0064	T
GERP RS		0.73
Varity_R		0.033
gMVP		0.41
Mutation Taster		=97/3	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: rs6901; hg19: chr10-3180227; COSMIC: COSV56528406; COSMIC: COSV56528406;