10-3143422-C-G

Variant names:

• chr10-3143422-C-G
• rs774144607
• NM_014889.4:c.2612G>C

Variant summary

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

The NM_014889.4(PITRM1):​c.2612G>C​(p.Arg871Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,864 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R871Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.46
• 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-AS1 (HGNC:44675): (PITRM1 antisense RNA 1)

ENSG00000278419 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2612G>C	p.Arg871Pro	missense	Exon 23 of 27	NP_055704.2
	PITRM1	NM_001242307.2		c.2615G>C	p.Arg872Pro	missense	Exon 23 of 27	NP_001229236.1	Q5JRX3-2
	PITRM1	NM_001347729.1		c.2588G>C	p.Arg863Pro	missense	Exon 23 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.2612G>C	p.Arg871Pro	missense	Exon 23 of 27	ENSP00000224949.4	Q5JRX3-1
	PITRM1	ENST00000380989.6	TSL:1	c.2615G>C	p.Arg872Pro	missense	Exon 23 of 27	ENSP00000370377.2	Q5JRX3-2
	PITRM1	ENST00000464395.1	TSL:1	n.2435G>C		non_coding_transcript_exon	Exon 5 of 9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460864 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726794

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33462

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

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

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111118

Other (OTH) AF: 0.00 AC: 0 AN: 60334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Benign	0.80
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.25
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.37
Sift	Benign	0.18	T
Sift4G	Benign	0.23	T
Polyphen		0.029	B
Vest4		0.95
MutPred		0.57		Gain of glycosylation at T872 (P = 0.0201)
MVP		0.40
MPC		0.099
ClinPred		0.69	D
GERP RS		5.0
Varity_R		0.82
gMVP		0.89
Mutation Taster		=19/81	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs774144607; hg19: chr10-3185614;