chr10-3166320-G-A

Variant names:

• chr10-3166320-G-A
• rs1127047
• NM_014889.4:c.327C>T

Variant summary

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

The NM_001347727.2(PITRM1):​c.-245C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,608,096 control chromosomes in the GnomAD database, including 1,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (239 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1273 hom.)
• Consequence: PITRM1 NM_001347727.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.55
• Publications: 11 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 (BayesDel_noAF=-0.85).
• BP6: Variant 10-3166320-G-A is Benign according to our data. Variant chr10-3166320-G-A is described in ClinVar as Benign. ClinVar VariationId is 1546017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0718 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001347727.2. 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.327C>T	p.Thr109Thr	synonymous	Exon 4 of 27	NP_055704.2
	PITRM1	NM_001347727.2		c.-245C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 27	NP_001334656.1
	PITRM1	NM_001347726.2		c.-245C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 25	NP_001334655.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PITRM1	ENST00000224949.9	TSL:1 MANE Select	c.327C>T	p.Thr109Thr	synonymous	Exon 4 of 27	ENSP00000224949.4
	PITRM1	ENST00000380989.6	TSL:1	c.327C>T	p.Thr109Thr	synonymous	Exon 4 of 27	ENSP00000370377.2
	PITRM1	ENST00000380994.6	TSL:5	c.-245C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 26	ENSP00000370382.2

Frequencies

GnomAD3 genomes AF: 0.0498 AC: 7441 AN: 149566 Hom.: 241 Cov.: 33

Gnomad AFR AF: 0.0740

Gnomad AMI AF: 0.0525

Gnomad AMR AF: 0.0666

Gnomad ASJ AF: 0.0316

Gnomad EAS AF: 0.0232

Gnomad SAS AF: 0.0424

Gnomad FIN AF: 0.0421

Gnomad MID AF: 0.0584

Gnomad NFE AF: 0.0356

Gnomad OTH AF: 0.0584

GnomAD2 exomes AF: 0.0469 AC: 11549 AN: 246376 AF XY: 0.0446

Gnomad AFR exome AF: 0.0740

Gnomad AMR exome AF: 0.0912

Gnomad ASJ exome AF: 0.0355

Gnomad EAS exome AF: 0.0232

Gnomad FIN exome AF: 0.0418

Gnomad NFE exome AF: 0.0354

Gnomad OTH exome AF: 0.0410

GnomAD4 exome AF: 0.0386 AC: 56266 AN: 1458406 Hom.: 1273 Cov.: 31 AF XY: 0.0384 AC XY: 27876 AN XY: 725612

African (AFR) AF: 0.0775 AC: 2585 AN: 33342

American (AMR) AF: 0.0865 AC: 3854 AN: 44580

Ashkenazi Jewish (ASJ) AF: 0.0342 AC: 892 AN: 26100

East Asian (EAS) AF: 0.0217 AC: 858 AN: 39620

South Asian (SAS) AF: 0.0481 AC: 4141 AN: 86042

European-Finnish (FIN) AF: 0.0413 AC: 2201 AN: 53264

Middle Eastern (MID) AF: 0.0436 AC: 250 AN: 5732

European-Non Finnish (NFE) AF: 0.0351 AC: 38944 AN: 1109464

Other (OTH) AF: 0.0422 AC: 2541 AN: 60262

GnomAD4 genome AF: 0.0498 AC: 7453 AN: 149690 Hom.: 239 Cov.: 33 AF XY: 0.0502 AC XY: 3663 AN XY: 73034

African (AFR) AF: 0.0740 AC: 3011 AN: 40714

American (AMR) AF: 0.0668 AC: 1004 AN: 15026

Ashkenazi Jewish (ASJ) AF: 0.0316 AC: 109 AN: 3448

East Asian (EAS) AF: 0.0233 AC: 118 AN: 5068

South Asian (SAS) AF: 0.0425 AC: 199 AN: 4684

European-Finnish (FIN) AF: 0.0421 AC: 434 AN: 10320

Middle Eastern (MID) AF: 0.0625 AC: 18 AN: 288

European-Non Finnish (NFE) AF: 0.0356 AC: 2392 AN: 67202

Other (OTH) AF: 0.0592 AC: 121 AN: 2044

Alfa AF: 0.0432 Hom.: 244

Bravo AF: 0.0539

Asia WGS AF: 0.0410 AC: 142 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.066
DANN	Benign	0.80
PhyloP100		-4.6
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1127047; hg19: chr10-3208512; COSMIC: COSV99828333; COSMIC: COSV99828333;