9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGCCGC

Position:

• chr9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGCCGC

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BA1

The ENST00000253008.3(PRDM12):​c.1074_1076dup​(p.Ala358dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.40 (11866 hom., cov: 0)
  • Exomes 𝑓: 0.29 (19887 hom.)
• Consequence: PRDM12 ENST00000253008.3 inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0910

Genes affected

PRDM12 (HGNC:13997): (PR/SET domain 12) This gene encodes a transcriptional regulator of sensory neuronal specification that plays a critical role in pain perception. The encoded protein contains an N-terminal PRDI-BF1 and RIZ homology (PR) domain, a SET domain, and three C-terminal C2H2 zinc finger DNA-binding domains. Naturally occurring mutations in this gene are associated with congenital insensitivity to pain (CIP), and hereditary sensory and autonomic neuropathies (HSAN's) affecting peripheral sensory and autonomic neurons. Deregulation of this gene is associated with solid cancers and hematological malignancies including chronic myeloid leukaemia. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in ENST00000253008.3
• BP6: Variant 9-130681605-T-TCGC is Benign according to our data. Variant chr9-130681605-T-TCGC is described in ClinVar as [Benign]. Clinvar id is 475813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM12	NM_021619.3	c.1074_1076dup	p.Ala358dup	inframe_insertion	5/5	ENST00000253008.3	NP_067632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM12	ENST00000253008.3	c.1074_1076dup	p.Ala358dup	inframe_insertion	5/5	1	NM_021619.3	ENSP00000253008	P1
PRDM12	ENST00000676323.1	c.906+168_906+170dup		intron_variant				ENSP00000502471

Frequencies

GnomAD3 genomes AF: 0.400 AC: 56728 AN: 141750 Hom.: 11863 Cov.: 0

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.322

Gnomad AMR AF: 0.480

Gnomad ASJ AF: 0.268

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.295

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.389

GnomAD4 exome AF: 0.291 AC: 234747 AN: 807512 Hom.: 19887 Cov.: 6 AF XY: 0.290 AC XY: 108501 AN XY: 374572

Gnomad4 AFR exome AF: 0.416

Gnomad4 AMR exome AF: 0.338

Gnomad4 ASJ exome AF: 0.230

Gnomad4 EAS exome AF: 0.402

Gnomad4 SAS exome AF: 0.378

Gnomad4 FIN exome AF: 0.0575

Gnomad4 NFE exome AF: 0.286

Gnomad4 OTH exome AF: 0.310

GnomAD4 genome AF: 0.400 AC: 56740 AN: 141788 Hom.: 11866 Cov.: 0 AF XY: 0.405 AC XY: 27848 AN XY: 68684

Gnomad4 AFR AF: 0.470

Gnomad4 AMR AF: 0.480

Gnomad4 ASJ AF: 0.268

Gnomad4 EAS AF: 0.608

Gnomad4 SAS AF: 0.461

Gnomad4 FIN AF: 0.392

Gnomad4 NFE AF: 0.330

Gnomad4 OTH AF: 0.392

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Congenital insensitivity to pain-hypohidrosis syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

PRDM12-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752427775; hg19: chr9-133556992;