10-3159873-T-G

Variant names:

• chr10-3159873-T-G
• rs4242746
• NM_014889.4:c.982A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014889.4(PITRM1):​c.982A>C​(p.Ile328Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,448,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. 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. I328V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.299

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)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20793185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITRM1	NM_014889.4	c.982A>C	p.Ile328Leu	missense_variant	Exon 9 of 27	ENST00000224949.9	NP_055704.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITRM1	ENST00000224949.9	c.982A>C	p.Ile328Leu	missense_variant	Exon 9 of 27	1	NM_014889.4	ENSP00000224949.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000424 AC: 1 AN: 235956 Hom.: 0 AF XY: 0.00000786 AC XY: 1 AN XY: 127242

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000942

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1448938 Hom.: 0 Cov.: 30 AF XY: 0.00000417 AC XY: 3 AN XY: 719926

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000830 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.3
DANN	Benign	0.93
DEOGEN2	Benign	0.017	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.58	T;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.59	N;N;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.020
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.35	T;T;T
Vest4		0.25
MutPred		0.44		Gain of disorder (P = 0.08);Gain of disorder (P = 0.08);.;
MVP		0.14
MPC		0.051
ClinPred		0.040	T
GERP RS		0.30
Varity_R		0.071
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4242746; hg19: chr10-3202065;