9-130681560-C-T

Position:

• chr9-130681560-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021619.3(PRDM12):​c.995C>T​(p.Ala332Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000555 in 1,224,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A332E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: PRDM12 NM_021619.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.49

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
• BP4: Computational evidence support a benign effect (MetaRNN=0.08067489).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRDM12	NM_021619.3	c.995C>T	p.Ala332Val	missense_variant	5/5	ENST00000253008.3	NP_067632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRDM12	ENST00000253008.3	c.995C>T	p.Ala332Val	missense_variant	5/5	1	NM_021619.3	ENSP00000253008.2
PRDM12	ENST00000676323.1	c.906+89C>T		intron_variant				ENSP00000502471.1

Frequencies

GnomAD3 genomes AF: 0.0000203 AC: 3 AN: 147910 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000301

Gnomad OTH AF: 0.000491

GnomAD4 exome AF: 0.0000604 AC: 65 AN: 1076318 Hom.: 0 Cov.: 31 AF XY: 0.0000668 AC XY: 34 AN XY: 508926

Gnomad4 AFR exome AF: 0.0000441

Gnomad4 AMR exome AF: 0.000121

Gnomad4 ASJ exome AF: 0.000425

Gnomad4 EAS exome AF: 0.0000380

Gnomad4 SAS exome AF: 0.0000953

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000545

Gnomad4 OTH exome AF: 0.0000462

GnomAD4 genome AF: 0.0000203 AC: 3 AN: 147910 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 72058

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000301

Gnomad4 OTH AF: 0.000491

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

Oct 24, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 332 of the PRDM12 protein (p.Ala332Val). This variant is present in population databases (no rsID available, gnomAD no frequency). 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: 577727). 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: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.023
Sift	Benign	0.051	T
Sift4G	Benign	0.34	T
Polyphen		0.0070	B
Vest4		0.21
MutPred		0.41		Loss of helix (P = 0.0033);
MVP		0.21
MPC		1.7
ClinPred		0.11	T
GERP RS		2.2
Varity_R		0.069
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs773010364; hg19: chr9-133556947;