10-3155664-C-G

Variant names:

• chr10-3155664-C-G
• rs3765101
• NM_014889.4:c.1548G>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.1548G>C​(p.Gln516His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0741 in 1,613,756 control chromosomes in the GnomAD database, including 6,538 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (581 hom., cov: 32)
  • Exomes 𝑓: 0.075 (5957 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.122
• Publications: 17 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=0.004927784).
• BP6: Variant 10-3155664-C-G is Benign according to our data. Variant chr10-3155664-C-G is described in ClinVar as Benign. ClinVar VariationId is 1601727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.283 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.1548G>C	p.Gln516His	missense	Exon 14 of 27	NP_055704.2
	PITRM1	NM_001242307.2		c.1548G>C	p.Gln516His	missense	Exon 14 of 27	NP_001229236.1	Q5JRX3-2
	PITRM1	NM_001347729.1		c.1524G>C	p.Gln508His	missense	Exon 14 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.1548G>C	p.Gln516His	missense	Exon 14 of 27	ENSP00000224949.4	Q5JRX3-1
	PITRM1	ENST00000380989.6	TSL:1	c.1548G>C	p.Gln516His	missense	Exon 14 of 27	ENSP00000370377.2	Q5JRX3-2
	PITRM1	ENST00000851395.1		c.1536G>C	p.Gln512His	missense	Exon 14 of 27	ENSP00000521454.1

Frequencies

GnomAD3 genomes AF: 0.0690 AC: 10489 AN: 152020 Hom.: 584 Cov.: 32

Gnomad AFR AF: 0.0308

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0822

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0608

Gnomad OTH AF: 0.0649

GnomAD2 exomes AF: 0.103 AC: 25720 AN: 249206 AF XY: 0.102

Gnomad AFR exome AF: 0.0320

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.0335

Gnomad EAS exome AF: 0.296

Gnomad FIN exome AF: 0.114

Gnomad NFE exome AF: 0.0606

Gnomad OTH exome AF: 0.0948

GnomAD4 exome AF: 0.0746 AC: 109036 AN: 1461618 Hom.: 5957 Cov.: 31 AF XY: 0.0762 AC XY: 55373 AN XY: 727096

African (AFR) AF: 0.0260 AC: 872 AN: 33478

American (AMR) AF: 0.141 AC: 6306 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0336 AC: 879 AN: 26136

East Asian (EAS) AF: 0.300 AC: 11904 AN: 39696

South Asian (SAS) AF: 0.144 AC: 12429 AN: 86252

European-Finnish (FIN) AF: 0.113 AC: 6053 AN: 53374

Middle Eastern (MID) AF: 0.0269 AC: 155 AN: 5766

European-Non Finnish (NFE) AF: 0.0592 AC: 65847 AN: 1111826

Other (OTH) AF: 0.0760 AC: 4591 AN: 60372

GnomAD4 genome AF: 0.0690 AC: 10495 AN: 152138 Hom.: 581 Cov.: 32 AF XY: 0.0736 AC XY: 5474 AN XY: 74384

African (AFR) AF: 0.0309 AC: 1285 AN: 41540

American (AMR) AF: 0.0822 AC: 1256 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 119 AN: 3470

East Asian (EAS) AF: 0.295 AC: 1515 AN: 5130

South Asian (SAS) AF: 0.160 AC: 771 AN: 4814

European-Finnish (FIN) AF: 0.116 AC: 1227 AN: 10592

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0607 AC: 4130 AN: 67990

Other (OTH) AF: 0.0666 AC: 141 AN: 2116

Alfa AF: 0.0645 Hom.: 347

Bravo AF: 0.0668

TwinsUK AF: 0.0599 AC: 222

ALSPAC AF: 0.0649 AC: 250

ESP6500AA AF: 0.0302 AC: 125

ESP6500EA AF: 0.0625 AC: 528

ExAC AF: 0.101 AC: 12155

Asia WGS AF: 0.202 AC: 698 AN: 3478

EpiCase AF: 0.0556

EpiControl AF: 0.0561

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.4
DANN	Benign	0.74
DEOGEN2	Benign	0.087	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.12
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.11
Sift	Benign	0.11	T
Sift4G	Benign	0.13	T
Polyphen		0.0010	B
Vest4		0.24
MutPred		0.44		Loss of MoRF binding (P = 0.1186)
MPC		0.049
ClinPred		0.020	T
GERP RS		-3.1
Varity_R		0.18
gMVP		0.29
Mutation Taster		=96/4	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: rs3765101; hg19: chr10-3197856; COSMIC: COSV56528174;