9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGC

Variant names:

• chr9-130681605-TCGC-T
• rs752427775
• NM_021619.3:c.1074_1076delCGC

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP3 BP6 BS1

The NM_021619.3(PRDM12):​c.1074_1076delCGC​(p.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 0.00148 in 942,186 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0016 (0 hom.)
• Consequence: PRDM12 NM_021619.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B: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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_021619.3
• BP6: Variant 9-130681605-TCGC-T is Benign according to our data. Variant chr9-130681605-TCGC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 648392.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}. Variant chr9-130681605-TCGC-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000775 (110/141916) while in subpopulation AFR AF= 0.00211 (83/39292). AF 95% confidence interval is 0.00175. There are 0 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM12	NM_021619.3	c.1074_1076delCGC	p.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.1074_1076delCGC	p.Ala359del	disruptive_inframe_deletion	Exon 5 of 5	1	NM_021619.3	ENSP00000253008.2
PRDM12	ENST00000676323.1	c.906+168_906+170delCGC		intron_variant	Intron 5 of 5			ENSP00000502471.1

Frequencies

GnomAD3 genomes AF: 0.000768 AC: 109 AN: 141876 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00107

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000256

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000248

Gnomad OTH AF: 0.00104

GnomAD4 exome AF: 0.00160 AC: 1281 AN: 800270 Hom.: 0 AF XY: 0.00162 AC XY: 601 AN XY: 371246

Gnomad4 AFR exome AF: 0.00369

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.00137

Gnomad4 EAS exome AF: 0.00203

Gnomad4 SAS exome AF: 0.000936

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00159

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.000775 AC: 110 AN: 141916 Hom.: 0 Cov.: 0 AF XY: 0.000814 AC XY: 56 AN XY: 68754

Gnomad4 AFR AF: 0.00211

Gnomad4 AMR AF: 0.000138

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00107

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000256

Gnomad4 NFE AF: 0.000248

Gnomad4 OTH AF: 0.00103

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital insensitivity to pain-hypohidrosis syndrome Uncertain:1

Oct 23, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1074_1076delCGC, results in the deletion of 1 amino acid(s) of the PRDM12 protein (p.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 ExAC database. This variant has not been reported in the literature in individuals with PRDM12-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid 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 Benign:1

Mar 10, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Aug 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs752427775; hg19: chr9-133556992;