rs773010364

chr9-130681560-C-Achr9-130681560-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 BP4_Strong BP6_Very_Strong BS1

The NM_021619.3(PRDM12):c.995C>A(p.Ala332Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,224,332 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A332V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (1 hom.)
• Consequence: PRDM12 NM_021619.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.00211972).
• BP6: Variant 9-130681560-C-A is Benign according to our data. Variant chr9-130681560-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 475818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-130681560-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00128 (189/148014) while in subpopulation NFE AF= 0.00206 (137/66520). AF 95% confidence interval is 0.00178. There are 0 homozygotes in gnomad4. There are 78 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM12	NM_021619.3	c.995C>A	p.Ala332Glu	missense_variant	5/5	ENST00000253008.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM12	ENST00000253008.3	c.995C>A	p.Ala332Glu	missense_variant	5/5	1	NM_021619.3	P1
PRDM12	ENST00000676323.1	c.906+89C>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 189 AN: 147910 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

Gnomad ASJ AF: 0.00117

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00315

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00147

GnomAD3 exomes AF: 0.00351 AC: 2 AN: 570 Hom.: 0 AF XY: 0.00524 AC XY: 2 AN XY: 382

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: 0.0435

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00168 AC: 1803 AN: 1076318 Hom.: 1 Cov.: 31 AF XY: 0.00166 AC XY: 847 AN XY: 508926

Gnomad4 AFR exome AF: 0.000221

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000283

Gnomad4 EAS exome AF: 0.0000380

Gnomad4 SAS exome AF: 0.0000477

Gnomad4 FIN exome AF: 0.00392

Gnomad4 NFE exome AF: 0.00183

Gnomad4 OTH exome AF: 0.000832

GnomAD4 genome AF: 0.00128 AC: 189 AN: 148014 Hom.: 0 Cov.: 32 AF XY: 0.00108 AC XY: 78 AN XY: 72174

Gnomad4 AFR AF: 0.000316

Gnomad4 AMR AF: 0.000134

Gnomad4 ASJ AF: 0.00117

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00315

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.00146

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.000854

ExAC AF: 0.00151 AC: 35

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital insensitivity to pain-hypohidrosis syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2021

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	20
Dann	Benign	0.97
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.71	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.23	N
REVEL	Benign	0.081
Sift	Benign	0.078	T
Sift4G	Benign	0.36	T
Polyphen		0.0020	B
Vest4		0.27
MVP		0.24
MPC		2.0
ClinPred		0.025	T
GERP RS		2.2
Varity_R		0.12
gMVP		0.52

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: rs773010364; hg19: chr9-133556947;