chr10-3165440-A-T

Variant names:

• chr10-3165440-A-T
• rs3814596
• NM_014889.4:c.506T>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014889.4(PITRM1):​c.506T>A​(p.Phe169Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. F169S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.66

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PITRM1	NM_014889.4	c.506T>A	p.Phe169Tyr	missense_variant	Exon 5 of 27	ENST00000224949.9	NP_055704.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PITRM1	ENST00000224949.9	c.506T>A	p.Phe169Tyr	missense_variant	Exon 5 of 27	1	NM_014889.4	ENSP00000224949.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458782 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725690

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.014	T;.;.
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.0027	T
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.85	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.92	T;T;T
Polyphen		0.34	B;B;.
Vest4		0.71
MutPred		0.54		Gain of catalytic residue at L164 (P = 0.1516);Gain of catalytic residue at L164 (P = 0.1516);.;
MVP		0.45
MPC		0.17
ClinPred		0.88	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.65

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: rs3814596; hg19: chr10-3207632;