chr10-3149631-C-T

Variant names:

• chr10-3149631-C-T
• rs2388556
• NM_014889.4:c.1861G>A

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.1861G>A​(p.Val621Ile) variant causes a missense change. The variant allele was found at a frequency of 0.165 in 1,566,790 control chromosomes in the GnomAD database, including 22,192 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V621V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (1763 hom., cov: 32)
  • Exomes 𝑓: 0.17 (20429 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.86
• Publications: 28 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=0.0022476315).
• BP6: Variant 10-3149631-C-T is Benign according to our data. Variant chr10-3149631-C-T is described in ClinVar as Benign. ClinVar VariationId is 1300268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.169 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.1861G>A	p.Val621Ile	missense	Exon 16 of 27	NP_055704.2
	PITRM1	NM_001242307.2		c.1861G>A	p.Val621Ile	missense	Exon 16 of 27	NP_001229236.1	Q5JRX3-2
	PITRM1	NM_001347729.1		c.1837G>A	p.Val613Ile	missense	Exon 16 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.1861G>A	p.Val621Ile	missense	Exon 16 of 27	ENSP00000224949.4	Q5JRX3-1
	PITRM1	ENST00000380989.6	TSL:1	c.1861G>A	p.Val621Ile	missense	Exon 16 of 27	ENSP00000370377.2	Q5JRX3-2
	PITRM1	ENST00000851395.1		c.1849G>A	p.Val617Ile	missense	Exon 16 of 27	ENSP00000521454.1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22716 AN: 151922 Hom.: 1762 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0999

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.0488

Gnomad SAS AF: 0.129

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.146

GnomAD2 exomes AF: 0.144 AC: 30838 AN: 213836 AF XY: 0.148

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.0701

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.0537

Gnomad FIN exome AF: 0.201

Gnomad NFE exome AF: 0.170

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.167 AC: 235926 AN: 1414750 Hom.: 20429 Cov.: 31 AF XY: 0.167 AC XY: 116664 AN XY: 700340

African (AFR) AF: 0.128 AC: 3990 AN: 31196

American (AMR) AF: 0.0762 AC: 2596 AN: 34066

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2642 AN: 23544

East Asian (EAS) AF: 0.0559 AC: 2173 AN: 38892

South Asian (SAS) AF: 0.144 AC: 11461 AN: 79450

European-Finnish (FIN) AF: 0.200 AC: 10491 AN: 52402

Middle Eastern (MID) AF: 0.122 AC: 667 AN: 5474

European-Non Finnish (NFE) AF: 0.177 AC: 193038 AN: 1091520

Other (OTH) AF: 0.152 AC: 8868 AN: 58206

GnomAD4 genome AF: 0.149 AC: 22714 AN: 152040 Hom.: 1763 Cov.: 32 AF XY: 0.149 AC XY: 11055 AN XY: 74310

African (AFR) AF: 0.134 AC: 5548 AN: 41458

American (AMR) AF: 0.0997 AC: 1524 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 419 AN: 3472

East Asian (EAS) AF: 0.0485 AC: 250 AN: 5154

South Asian (SAS) AF: 0.129 AC: 623 AN: 4820

European-Finnish (FIN) AF: 0.211 AC: 2231 AN: 10566

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.172 AC: 11680 AN: 67970

Other (OTH) AF: 0.145 AC: 306 AN: 2112

Alfa AF: 0.156 Hom.: 6664

Bravo AF: 0.138

TwinsUK AF: 0.174 AC: 647

ALSPAC AF: 0.164 AC: 632

ESP6500AA AF: 0.130 AC: 532

ESP6500EA AF: 0.172 AC: 1444

ExAC AF: 0.143 AC: 17253

Asia WGS AF: 0.0830 AC: 290 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	PITRM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.085
Sift	Benign	0.18	T
Sift4G	Benign	0.17	T
Polyphen		0.97	D
Vest4		0.14
MPC		0.11
ClinPred		0.017	T
GERP RS		4.5
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.42
Mutation Taster		=86/14	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: rs2388556; hg19: chr10-3191823; COSMIC: COSV56528731; COSMIC: COSV56528731;