chr9-130681605-TCGCCGCCGCCGCCGCCGCCGC-T

Variant names:

• chr9-130681605-TCGCCGCCGCCGCCGCCGCCGC-T
• rs752427775
• NM_021619.3:c.1056_1076delCGCCGCCGCCGCCGCCGCCGC

Variant summary

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

The NM_021619.3(PRDM12):​c.1056_1076delCGCCGCCGCCGCCGCCGCCGC​(p.Ala353_Ala359del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000892 in 955,252 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00097 (1 hom.)
• Consequence: PRDM12 NM_021619.3 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.33

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 NM_021619.3
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000973 (791/813336) while in subpopulation EAS AF= 0.00152 (6/3958). AF 95% confidence interval is 0.000954. There are 1 homozygotes in gnomad4_exome. There are 386 alleles in male gnomad4_exome subpopulation. 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 rank	MANE	Protein	UniProt
PRDM12	NM_021619.3	c.1056_1076delCGCCGCCGCCGCCGCCGCCGC	p.Ala353_Ala359del	disruptive_inframe_deletion	Exon 5 of 5	ENST00000253008.3	NP_067632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM12	ENST00000253008.3	c.1056_1076delCGCCGCCGCCGCCGCCGCCGC	p.Ala353_Ala359del	disruptive_inframe_deletion	Exon 5 of 5	1	NM_021619.3	ENSP00000253008.2
PRDM12	ENST00000676323.1	c.906+150_906+170delCGCCGCCGCCGCCGCCGCCGC		intron_variant	Intron 5 of 5			ENSP00000502471.1

Frequencies

GnomAD3 genomes AF: 0.000430 AC: 61 AN: 141876 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000536

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000277

Gnomad ASJ AF: 0.000299

Gnomad EAS AF: 0.000639

Gnomad SAS AF: 0.000433

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000433

Gnomad OTH AF: 0.00104

GnomAD4 exome AF: 0.000973 AC: 791 AN: 813336 Hom.: 1 AF XY: 0.00102 AC XY: 386 AN XY: 377254

Gnomad4 AFR exome AF: 0.000405

Gnomad4 AMR exome AF: 0.000785

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00152

Gnomad4 SAS exome AF: 0.000555

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.000598

GnomAD4 genome AF: 0.000430 AC: 61 AN: 141916 Hom.: 0 Cov.: 0 AF XY: 0.000451 AC XY: 31 AN XY: 68754

Gnomad4 AFR AF: 0.000534

Gnomad4 AMR AF: 0.000276

Gnomad4 ASJ AF: 0.000299

Gnomad4 EAS AF: 0.000641

Gnomad4 SAS AF: 0.000434

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000433

Gnomad4 OTH AF: 0.00103

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

Jul 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1056_1076del, results in the deletion of 7 amino acid(s) of the PRDM12 protein (p.Ala353_Ala359del), 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 insufficient coverage 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: 475805). 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

Feb 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1056_1076del21 (p.A353_A359del) alteration is located in exon 5 (coding exon 5) of the PRDM12 gene. This alteration consists of an in-frame deletion of 21 nucleotides between nucleotide positions c.1056 and c.1076, resulting in the deletion of 7 residues. 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: rs752427775; hg19: chr9-133556992;