rs1429038624

Positions:

• chr9-130681607-G-GCCA

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP3 BS1_Supporting

The ENST00000253008.3(PRDM12):​c.1044_1045insACC​(p.Ala348_Ala349insThr) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 662,116 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000056 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PRDM12 ENST00000253008.3 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.595

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in ENST00000253008.3
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000564 (7/124006) while in subpopulation EAS AF= 0.00237 (7/2952). AF 95% confidence interval is 0.00111. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM12	NM_021619.3	c.1044_1045insACC	p.Ala348_Ala349insThr	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.1044_1045insACC	p.Ala348_Ala349insThr	inframe_insertion	5/5	1	NM_021619.3	ENSP00000253008	P1
PRDM12	ENST00000676323.1	c.906+138_906+139insACC		intron_variant				ENSP00000502471

Frequencies

GnomAD3 genomes AF: 0.0000565 AC: 7 AN: 123948 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00237

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000167 AC: 9 AN: 538110 Hom.: 0 Cov.: 6 AF XY: 0.0000121 AC XY: 3 AN XY: 248358

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00444

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000203

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000564 AC: 7 AN: 124006 Hom.: 0 Cov.: 30 AF XY: 0.0000996 AC XY: 6 AN XY: 60212

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00237

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital insensitivity to pain-hypohidrosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2022

This variant, c.1044_1045insACC, results in the insertion of 1 amino acid(s) of the PRDM12 protein (p.Ala348_Ala349insThr), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PRDM12-related conditions. ClinVar contains an entry for this variant (Variation ID: 475804). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2023

The c.1044_1045insACC (p.A348_A349insT) alteration, located in coding exon 5 of the PRDM12 gene, results from an in-frame insertion of 3 nucleotides at positions c.1044 to c.1045. This results in the insertion of a threonine residue at p.348 to p.349. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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: rs1429038624; hg19: chr9-133556994;