rs59654932

Variant names:

• chr10-3144334-G-C
• rs59654932
• NM_014889.4:c.2490C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-3144334-G-C
• chr10-3144334-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014889.4(PITRM1):​c.2490C>G​(p.Ala830Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00812 in 1,562,510 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0084 (85 hom.)
• Consequence: PITRM1 NM_014889.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.66
• Publications: 4 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.005).
• BP6: Variant 10-3144334-G-C is Benign according to our data. Variant chr10-3144334-G-C is described in ClinVar as Benign. ClinVar VariationId is 1666348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0084 (11847/1410348) while in subpopulation MID AF = 0.0241 (138/5722). AF 95% confidence interval is 0.0208. There are 85 homozygotes in GnomAdExome4. There are 6015 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.2490C>G	p.Ala830Ala	synonymous	Exon 22 of 27	NP_055704.2
	PITRM1	NM_001242307.2		c.2493C>G	p.Ala831Ala	synonymous	Exon 22 of 27	NP_001229236.1	Q5JRX3-2
	PITRM1	NM_001347729.1		c.2466C>G	p.Ala822Ala	synonymous	Exon 22 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.2490C>G	p.Ala830Ala	synonymous	Exon 22 of 27	ENSP00000224949.4	Q5JRX3-1
	PITRM1	ENST00000380989.6	TSL:1	c.2493C>G	p.Ala831Ala	synonymous	Exon 22 of 27	ENSP00000370377.2	Q5JRX3-2
	PITRM1	ENST00000464395.1	TSL:1	n.2083C>G		non_coding_transcript_exon	Exon 4 of 9

Frequencies

GnomAD3 genomes AF: 0.00555 AC: 844 AN: 152044 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.0108

Gnomad SAS AF: 0.0127

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00772

Gnomad OTH AF: 0.00765

GnomAD2 exomes AF: 0.00777 AC: 1352 AN: 174066 AF XY: 0.00885

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.00404

Gnomad ASJ exome AF: 0.0194

Gnomad EAS exome AF: 0.00969

Gnomad FIN exome AF: 0.000969

Gnomad NFE exome AF: 0.00767

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00840 AC: 11847 AN: 1410348 Hom.: 85 Cov.: 29 AF XY: 0.00863 AC XY: 6015 AN XY: 696768

African (AFR) AF: 0.00159 AC: 51 AN: 32098

American (AMR) AF: 0.00379 AC: 143 AN: 37766

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 472 AN: 25284

East Asian (EAS) AF: 0.0107 AC: 395 AN: 36930

South Asian (SAS) AF: 0.0144 AC: 1154 AN: 79946

European-Finnish (FIN) AF: 0.00116 AC: 58 AN: 50040

Middle Eastern (MID) AF: 0.0241 AC: 138 AN: 5722

European-Non Finnish (NFE) AF: 0.00820 AC: 8891 AN: 1084108

Other (OTH) AF: 0.00932 AC: 545 AN: 58454

GnomAD4 genome AF: 0.00553 AC: 842 AN: 152162 Hom.: 5 Cov.: 33 AF XY: 0.00512 AC XY: 381 AN XY: 74400

African (AFR) AF: 0.00130 AC: 54 AN: 41510

American (AMR) AF: 0.00373 AC: 57 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.0106 AC: 55 AN: 5186

South Asian (SAS) AF: 0.0127 AC: 61 AN: 4812

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10586

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.00772 AC: 525 AN: 67992

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00891 Hom.: 1

Bravo AF: 0.00535

Asia WGS AF: 0.0140 AC: 49 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
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.091
DANN	Benign	0.48
PhyloP100		-2.7
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs59654932; hg19: chr10-3186526; COSMIC: COSV56540268;