10-3138239-C-G

Variant names:

• chr10-3138239-C-G
• rs758352717
• NM_014889.4:c.3016G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014889.4(PITRM1):​c.3016G>C​(p.Asp1006His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,612,076 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.240
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09777892).

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.3016G>C	p.Asp1006His	missense	Exon 26 of 27	NP_055704.2
	PITRM1	NM_001242307.2		c.3019G>C	p.Asp1007His	missense	Exon 26 of 27	NP_001229236.1	Q5JRX3-2
	PITRM1	NM_001347729.1		c.2992G>C	p.Asp998His	missense	Exon 26 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.3016G>C	p.Asp1006His	missense	Exon 26 of 27	ENSP00000224949.4	Q5JRX3-1
	PITRM1	ENST00000380989.6	TSL:1	c.3019G>C	p.Asp1007His	missense	Exon 26 of 27	ENSP00000370377.2	Q5JRX3-2
	PITRM1	ENST00000464395.1	TSL:1	n.2839G>C		non_coding_transcript_exon	Exon 8 of 9

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000309

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000883 AC: 22 AN: 249114 AF XY: 0.0000962

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 162 AN: 1459854 Hom.: 0 Cov.: 31 AF XY: 0.000112 AC XY: 81 AN XY: 726394

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000143 AC: 159 AN: 1110188

Other (OTH) AF: 0.0000332 AC: 2 AN: 60328

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000325 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000743 AC: 9

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	2.0
DANN	Benign	0.67
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.44	N
PhyloP100		0.24
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.031
Sift	Benign	0.20	T
Sift4G	Benign	0.10	T
Polyphen		0.0	B
Vest4		0.25
MVP		0.16
MPC		0.058
ClinPred		0.052	T
GERP RS		-5.4
Varity_R		0.14
gMVP		0.47
Mutation Taster		=82/18	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: rs758352717; hg19: chr10-3180431;