10-3138124-T-C

Variant names:

• chr10-3138124-T-C
• rs11414
• NM_014889.4:c.3021A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014889.4(PITRM1):​c.3021A>G​(p.Arg1007Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 1,598,882 control chromosomes in the GnomAD database, including 281,935 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29132 hom., cov: 32)
  • Exomes 𝑓: 0.59 (252803 hom.)
• Consequence: PITRM1 NM_014889.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00003535
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.360
• Publications: 21 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 10-3138124-T-C is Benign according to our data. Variant chr10-3138124-T-C is described in ClinVar as Benign. ClinVar VariationId is 1600344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.677 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.3021A>G	p.Arg1007Arg	splice_region synonymous	Exon 27 of 27	NP_055704.2
	PITRM1	NM_001242307.2		c.3024A>G	p.Arg1008Arg	splice_region synonymous	Exon 27 of 27	NP_001229236.1	Q5JRX3-2
	PITRM1	NM_001347729.1		c.2997A>G	p.Arg999Arg	splice_region synonymous	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.3021A>G	p.Arg1007Arg	splice_region synonymous	Exon 27 of 27	ENSP00000224949.4	Q5JRX3-1
	PITRM1	ENST00000380989.6	TSL:1	c.3024A>G	p.Arg1008Arg	splice_region synonymous	Exon 27 of 27	ENSP00000370377.2	Q5JRX3-2
	PITRM1	ENST00000464395.1	TSL:1	n.2844A>G		splice_region non_coding_transcript_exon	Exon 9 of 9

Frequencies

GnomAD3 genomes AF: 0.617 AC: 93831 AN: 151960 Hom.: 29106 Cov.: 32

Gnomad AFR AF: 0.683

Gnomad AMI AF: 0.584

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.595

Gnomad OTH AF: 0.612

GnomAD2 exomes AF: 0.592 AC: 141822 AN: 239608 AF XY: 0.590

Gnomad AFR exome AF: 0.684

Gnomad AMR exome AF: 0.573

Gnomad ASJ exome AF: 0.561

Gnomad EAS exome AF: 0.515

Gnomad FIN exome AF: 0.678

Gnomad NFE exome AF: 0.598

Gnomad OTH exome AF: 0.603

GnomAD4 exome AF: 0.589 AC: 852281 AN: 1446804 Hom.: 252803 Cov.: 33 AF XY: 0.587 AC XY: 422561 AN XY: 719676

African (AFR) AF: 0.691 AC: 22938 AN: 33172

American (AMR) AF: 0.578 AC: 25285 AN: 43774

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 14333 AN: 25866

East Asian (EAS) AF: 0.527 AC: 20793 AN: 39476

South Asian (SAS) AF: 0.537 AC: 45613 AN: 84948

European-Finnish (FIN) AF: 0.671 AC: 35551 AN: 53002

Middle Eastern (MID) AF: 0.606 AC: 3480 AN: 5738

European-Non Finnish (NFE) AF: 0.590 AC: 649197 AN: 1100902

Other (OTH) AF: 0.586 AC: 35091 AN: 59926

GnomAD4 genome AF: 0.617 AC: 93903 AN: 152078 Hom.: 29132 Cov.: 32 AF XY: 0.616 AC XY: 45773 AN XY: 74334

African (AFR) AF: 0.683 AC: 28343 AN: 41482

American (AMR) AF: 0.580 AC: 8863 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1920 AN: 3464

East Asian (EAS) AF: 0.514 AC: 2642 AN: 5144

South Asian (SAS) AF: 0.536 AC: 2579 AN: 4816

European-Finnish (FIN) AF: 0.672 AC: 7106 AN: 10582

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.595 AC: 40462 AN: 67980

Other (OTH) AF: 0.610 AC: 1288 AN: 2110

Alfa AF: 0.597 Hom.: 92611

Bravo AF: 0.614

Asia WGS AF: 0.521 AC: 1813 AN: 3478

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.5
DANN	Benign	0.74
PhyloP100		0.36
Mutation Taster		=58/42	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.0020
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: rs11414; hg19: chr10-3180316; COSMIC: COSV56527721; COSMIC: COSV56527721;