chr9-130681560-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

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. 14/21 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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.49

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

congenital insensitivity to pain-hypohidrosis syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
hereditary sensory and autonomic neuropathy
Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina

PRDM12 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

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 VariationId is 475818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021619.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM12	NM_021619.3	MANE Select	c.995C>A	p.Ala332Glu	missense	Exon 5 of 5	NP_067632.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM12	ENST00000253008.3	TSL:1 MANE Select	c.995C>A	p.Ala332Glu	missense	Exon 5 of 5	ENSP00000253008.2	Q9H4Q4
	PRDM12	ENST00000676323.1		c.906+89C>A		intron	N/A	ENSP00000502471.1	A0A6Q8PH01

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

189

AN:

147910

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00351

AC:

AN:

570

AF XY:

0.00524

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 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.:

Cov.:

AF XY:

0.00166

AC XY:

847

AN XY:

508926

show subpopulations

African (AFR)

AF:

0.000221

AC:

AN:

22672

American (AMR)

AF:

0.00

AC:

AN:

8242

Ashkenazi Jewish (ASJ)

AF:

0.000283

AC:

AN:

14118

East Asian (EAS)

AF:

0.0000380

AC:

AN:

26306

South Asian (SAS)

AF:

0.0000477

AC:

AN:

20982

European-Finnish (FIN)

AF:

0.00392

AC:

AN:

21188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2896

European-Non Finnish (NFE)

AF:

0.00183

AC:

1673

AN:

916628

Other (OTH)

AF:

0.000832

AC:

AN:

43286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

104

209

313

418

522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00128

AC:

189

AN:

148014

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

AN XY:

72174

show subpopulations

African (AFR)

AF:

0.000316

AC:

AN:

41098

American (AMR)

AF:

0.000134

AC:

AN:

14908

Ashkenazi Jewish (ASJ)

AF:

0.00117

AC:

AN:

3420

East Asian (EAS)

AF:

0.000196

AC:

AN:

5098

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00315

AC:

AN:

8894

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00206

AC:

137

AN:

66520

Other (OTH)

AF:

0.00146

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.000854

ExAC

AF:

0.00151

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital insensitivity to pain-hypohidrosis syndrome (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.0085

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.60

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

1.5

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

0.23

REVEL

Benign

0.081

Sift

Benign

0.078

Sift4G

Benign

0.36

Polyphen

0.0020

Vest4

0.27

MVP

0.24

MPC

2.0

ClinPred

0.025

GERP RS

2.2

Varity_R

0.12

gMVP

0.52

Mutation Taster

=89/11

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over