9-130664673-C-T

Position:

• chr9-130664673-C-T

Variant summary

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

The NM_021619.3(PRDM12):​c.20C>T​(p.Pro7Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000276 in 1,447,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: PRDM12 NM_021619.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.32

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM12	NM_021619.3	c.20C>T	p.Pro7Leu	missense_variant	1/5	ENST00000253008.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM12	ENST00000253008.3	c.20C>T	p.Pro7Leu	missense_variant	1/5	1	NM_021619.3	P1
PRDM12	ENST00000676323.1	c.20C>T	p.Pro7Leu	missense_variant	1/6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1447838 Hom.: 0 Cov.: 34 AF XY: 0.00000278 AC XY: 2 AN XY: 719776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital insensitivity to pain-hypohidrosis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 20, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with PRDM12-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 7 of the PRDM12 protein (p.Pro7Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.083	T
Eigen	Benign	0.082
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.22
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.93	P
Vest4		0.73
MutPred		0.41		Loss of disorder (P = 0.0406);
MVP		0.37
MPC		1.9
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.40
gMVP		0.70

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: rs779277068; hg19: chr9-133540060;