chr10-3138084-G-T

Variant names:

• chr10-3138084-G-T
• rs2131789083
• NM_014889.4:c.3061C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014889.4(PITRM1):​c.3061C>A​(p.Leu1021Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L1021L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.30
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26158333).

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.3061C>A	p.Leu1021Ile	missense	Exon 27 of 27	NP_055704.2
	PITRM1	NM_001242307.2		c.3064C>A	p.Leu1022Ile	missense	Exon 27 of 27	NP_001229236.1	Q5JRX3-2
	PITRM1	NM_001347729.1		c.3037C>A	p.Leu1013Ile	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.3061C>A	p.Leu1021Ile	missense	Exon 27 of 27	ENSP00000224949.4	Q5JRX3-1
	PITRM1	ENST00000380989.6	TSL:1	c.3064C>A	p.Leu1022Ile	missense	Exon 27 of 27	ENSP00000370377.2	Q5JRX3-2
	PITRM1	ENST00000464395.1	TSL:1	n.2884C>A		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.85
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.12
Sift	Benign	0.55	T
Sift4G	Benign	0.41	T
Polyphen		0.010	B
Vest4		0.41
MutPred		0.45		Gain of catalytic residue at P1023 (P = 0.0441)
MVP		0.55
MPC		0.068
ClinPred		0.53	D
GERP RS		4.9
Varity_R		0.44
gMVP		0.53
Mutation Taster		=60/40	polymorphism

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: rs2131789083; hg19: chr10-3180276;