Variant 9-130664655-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_021619.3(PRDM12):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000437 in 1,372,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000024 ( 0 hom. )

Consequence

PRDM12
NM_021619.3 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.45

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

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 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/5	ENST00000253008.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM12	ENST00000253008.3 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/5	1	NM_021619.3	P1
PRDM12	ENST00000676323.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/6

Frequencies

GnomAD3 genomes

AF:

0.0000205

AC:

AN:

146634

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000747

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000501

AC:

AN:

199754

Hom.:

AF XY:

0.00000897

AC XY:

AN XY:

111514

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000245

AC:

AN:

1225892

Hom.:

Cov.:

AF XY:

0.00000330

AC XY:

AN XY:

606978

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000123

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000205

AC:

AN:

146634

Hom.:

Cov.:

AF XY:

0.0000140

AC XY:

AN XY:

71454

show subpopulations

Gnomad4 AFR

AF:

0.0000747

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000170

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2023

The c.2T>C (p.M1?) alteration is located in coding exon 1 of the PRDM12 gene and consists of a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an in-frame methionine one amino acid from the initiation site, which may result in N-terminal truncation of unknown functional significance. Based on data from gnomAD, the C allele has an overall frequency of 0.001% (1/199754) total alleles studied. The highest observed frequency was 0.001% (1/86632) of European (non-Finnish) alleles. This amino acid position is well conserved in available vertebrate species. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Benign

0.95

DEOGEN2

Benign

0.0047

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.019

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.97

PROVEAN

Benign

-0.41

REVEL

Benign

0.22

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0090

Vest4

0.89

MutPred

0.99

Gain of glycosylation at M1 (P = 0.0062);

MVP

0.22

ClinPred

0.96

GERP RS

3.2

Varity_R

0.79

gMVP

0.47

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

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