Variant 9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP5_ModerateBP3

The NM_021619.3(PRDM12):c.1059_1076dupCGCCGCCGCCGCCGCCGC(p.Ala354_Ala359dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00025 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PRDM12
NM_021619.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.0910

Variant links:

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]

PRDM12 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP5

Variant 9-130681605-T-TCGCCGCCGCCGCCGCCGC is Pathogenic according to our data. Variant chr9-130681605-T-TCGCCGCCGCCGCCGCCGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 848182.Status of the report is criteria_provided_single_submitter, 1 stars.

BP3

Nonframeshift variant in repetitive region in NM_021619.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM12	NM_021619.3 link	c.1059_1076dupCGCCGCCGCCGCCGCCGC	p.Ala354_Ala359dup	disruptive_inframe_insertion	Exon 5 of 5	ENST00000253008.3	NP_067632.2	Q9H4Q4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM12	ENST00000253008.3 link	c.1059_1076dupCGCCGCCGCCGCCGCCGC	p.Ala354_Ala359dup	disruptive_inframe_insertion	Exon 5 of 5	1	NM_021619.3	ENSP00000253008.2		Q9H4Q4
PRDM12	ENST00000676323.1 link	c.906+153_906+170dupCGCCGCCGCCGCCGCCGC		intron_variant	Intron 5 of 5			ENSP00000502471.1		A0A6Q8PH01

Frequencies

GnomAD3 genomes

AF:

0.000303

AC:

AN:

141872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000408

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000691

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000256

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000356

Gnomad OTH

AF:

0.000518

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000247

AC:

201

AN:

813276

Hom.:

Cov.:

AF XY:

0.000233

AC XY:

AN XY:

377226

show subpopulations

Gnomad4 AFR exome

AF:

0.000135

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000253

Gnomad4 OTH exome

AF:

0.000374

GnomAD4 genome

AF:

0.000303

AC:

AN:

141912

Hom.:

Cov.:

AF XY:

0.000233

AC XY:

AN XY:

68754

show subpopulations

Gnomad4 AFR

AF:

0.000407

Gnomad4 AMR

AF:

0.0000691

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000256

Gnomad4 NFE

AF:

0.000356

Gnomad4 OTH

AF:

0.000514

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital insensitivity to pain-hypohidrosis syndrome

Pathogenic:1

Aug 23, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has been reported to have conflicting or insufficient data to determine the effect on PRDM12 protein function (PMID:26005867). This variant has been observed in individual(s) with autosomal recessive congenital insensitivity to pain (CIP) or midface toddler excoriation syndrome (MiTES) (PMID: 26005867, 31128170). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 848182). 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, c.1059_1076dup, results in the insertion of 6 amino acid(s) to the PRDM12 protein (p.Ala354_Ala359dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over