10-3165440-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014889.4(PITRM1):​c.506T>C​(p.Phe169Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,610,222 control chromosomes in the GnomAD database, including 28,845 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2217 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26628 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 8.66
• Publications: 27 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0032638013).
• BP6: Variant 10-3165440-A-G is Benign according to our data. Variant chr10-3165440-A-G is described in ClinVar as Benign. ClinVar VariationId is 1600892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

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.506T>C	p.Phe169Ser	missense	Exon 5 of 27	NP_055704.2
	PITRM1	NM_001242307.2		c.506T>C	p.Phe169Ser	missense	Exon 5 of 27	NP_001229236.1	Q5JRX3-2
	PITRM1	NM_001347729.1		c.482T>C	p.Phe161Ser	missense	Exon 5 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.506T>C	p.Phe169Ser	missense	Exon 5 of 27	ENSP00000224949.4	Q5JRX3-1
	PITRM1	ENST00000380989.6	TSL:1	c.506T>C	p.Phe169Ser	missense	Exon 5 of 27	ENSP00000370377.2	Q5JRX3-2
	PITRM1	ENST00000851395.1		c.506T>C	p.Phe169Ser	missense	Exon 5 of 27	ENSP00000521454.1

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25534 AN: 152078 Hom.: 2216 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.209

Gnomad EAS AF: 0.0506

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.175

GnomAD2 exomes AF: 0.166 AC: 41123 AN: 247752 AF XY: 0.172

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.0818

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.0550

Gnomad FIN exome AF: 0.221

Gnomad NFE exome AF: 0.194

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.188 AC: 273490 AN: 1458026 Hom.: 26628 Cov.: 31 AF XY: 0.188 AC XY: 136520 AN XY: 725350

African (AFR) AF: 0.137 AC: 4568 AN: 33374

American (AMR) AF: 0.0880 AC: 3921 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 5261 AN: 26072

East Asian (EAS) AF: 0.0563 AC: 2232 AN: 39678

South Asian (SAS) AF: 0.183 AC: 15719 AN: 85946

European-Finnish (FIN) AF: 0.215 AC: 11493 AN: 53376

Middle Eastern (MID) AF: 0.184 AC: 1061 AN: 5760

European-Non Finnish (NFE) AF: 0.197 AC: 218674 AN: 1109016

Other (OTH) AF: 0.175 AC: 10561 AN: 60254

GnomAD4 genome AF: 0.168 AC: 25535 AN: 152196 Hom.: 2217 Cov.: 32 AF XY: 0.166 AC XY: 12373 AN XY: 74398

African (AFR) AF: 0.143 AC: 5938 AN: 41526

American (AMR) AF: 0.118 AC: 1803 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 726 AN: 3468

East Asian (EAS) AF: 0.0503 AC: 261 AN: 5184

South Asian (SAS) AF: 0.174 AC: 834 AN: 4804

European-Finnish (FIN) AF: 0.224 AC: 2377 AN: 10594

Middle Eastern (MID) AF: 0.167 AC: 49 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13058 AN: 68006

Other (OTH) AF: 0.174 AC: 367 AN: 2112

Alfa AF: 0.180 Hom.: 10033

Bravo AF: 0.156

TwinsUK AF: 0.200 AC: 741

ALSPAC AF: 0.192 AC: 741

ESP6500AA AF: 0.140 AC: 523

ESP6500EA AF: 0.194 AC: 1599

ExAC AF: 0.168 AC: 20283

Asia WGS AF: 0.0990 AC: 347 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	PITRM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		8.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.17
Sift	Benign	0.20	T
Sift4G	Benign	0.43	T
Polyphen		0.75	P
Vest4		0.36
MPC		0.40
ClinPred		0.037	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.79
Mutation Taster		=71/29	polymorphism (auto)

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: rs3814596; hg19: chr10-3207632; COSMIC: COSV56529367; COSMIC: COSV56529367;