NM_014889.4:c.3049G>A

Variant names:

• chr10-3138096-C-T
• rs35779348
• NM_014889.4:c.3049G>A

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.3049G>A​(p.Gly1017Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0262 in 1,609,880 control chromosomes in the GnomAD database, including 672 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 0.019 (40 hom., cov: 34)
  • Exomes 𝑓: 0.027 (632 hom.)
• Consequence: PITRM1 NM_014889.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.84
• Publications: 14 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 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia, autosomal recessive 30

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Illumina, Labcorp Genetics (formerly Invitae)

ENSG00000278419 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0100236535).
• BP6: Variant 10-3138096-C-T is Benign according to our data. Variant chr10-3138096-C-T is described in ClinVar as Benign. ClinVar VariationId is 1628450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0188 (2866/152290) while in subpopulation NFE AF = 0.0307 (2089/68030). AF 95% confidence interval is 0.0296. There are 40 homozygotes in GnomAd4. There are 1258 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 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.3049G>A	p.Gly1017Ser	missense	Exon 27 of 27	NP_055704.2
	PITRM1	NM_001242307.2		c.3052G>A	p.Gly1018Ser	missense	Exon 27 of 27	NP_001229236.1	Q5JRX3-2
	PITRM1	NM_001347729.1		c.3025G>A	p.Gly1009Ser	missense	Exon 27 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.3049G>A	p.Gly1017Ser	missense	Exon 27 of 27	ENSP00000224949.4	Q5JRX3-1
	PITRM1	ENST00000380989.6	TSL:1	c.3052G>A	p.Gly1018Ser	missense	Exon 27 of 27	ENSP00000370377.2	Q5JRX3-2
	PITRM1	ENST00000464395.1	TSL:1	n.2872G>A		non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes AF: 0.0188 AC: 2867 AN: 152172 Hom.: 40 Cov.: 34

Gnomad AFR AF: 0.00586

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0186

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0180 AC: 4374 AN: 242422 AF XY: 0.0184

Gnomad AFR exome AF: 0.00446

Gnomad AMR exome AF: 0.0122

Gnomad ASJ exome AF: 0.0108

Gnomad EAS exome AF: 0.000226

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.0304

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.0270 AC: 39326 AN: 1457590 Hom.: 632 Cov.: 34 AF XY: 0.0264 AC XY: 19128 AN XY: 724570

African (AFR) AF: 0.00488 AC: 163 AN: 33416

American (AMR) AF: 0.0139 AC: 615 AN: 44314

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 303 AN: 25966

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39612

South Asian (SAS) AF: 0.00249 AC: 212 AN: 85176

European-Finnish (FIN) AF: 0.0127 AC: 676 AN: 53182

Middle Eastern (MID) AF: 0.0165 AC: 95 AN: 5766

European-Non Finnish (NFE) AF: 0.0323 AC: 35870 AN: 1109926

Other (OTH) AF: 0.0230 AC: 1387 AN: 60232

GnomAD4 genome AF: 0.0188 AC: 2866 AN: 152290 Hom.: 40 Cov.: 34 AF XY: 0.0169 AC XY: 1258 AN XY: 74480

African (AFR) AF: 0.00585 AC: 243 AN: 41558

American (AMR) AF: 0.0186 AC: 284 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.0118 AC: 125 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0307 AC: 2089 AN: 68030

Other (OTH) AF: 0.0251 AC: 53 AN: 2112

Alfa AF: 0.0265 Hom.: 131

Bravo AF: 0.0191

TwinsUK AF: 0.0353 AC: 131

ALSPAC AF: 0.0309 AC: 119

ESP6500AA AF: 0.00611 AC: 26

ESP6500EA AF: 0.0314 AC: 266

ExAC AF: 0.0176 AC: 2133

Asia WGS AF: 0.00231 AC: 8 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.8
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.20
Sift	Benign	0.051	T
Sift4G	Uncertain	0.056	T
Polyphen		0.99	D
Vest4		0.14
MPC		0.061
ClinPred		0.039	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.77
Mutation Taster		=76/24	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: rs35779348; hg19: chr10-3180288; COSMIC: COSV108081420; COSMIC: COSV108081420;