Genetic Variant PRDM12:p.Ala359dup (chr9-130681605-T-TCGC) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

The NM_021619.3(PRDM12):c.1074_1076dupCGC(p.Ala359dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A359A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.40 ( 11866 hom., cov: 0)

Exomes 𝑓: 0.29 ( 19887 hom. )

Consequence

PRDM12
NM_021619.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.0910

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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_021619.3

BP6

Variant 9-130681605-T-TCGC is Benign according to our data. Variant chr9-130681605-T-TCGC is described in ClinVar as Benign. ClinVar VariationId is 475813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

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.1074_1076dupCGC	p.Ala359dup	disruptive_inframe_insertion	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.1074_1076dupCGC	p.Ala359dup	disruptive_inframe_insertion	Exon 5 of 5	ENSP00000253008.2	Q9H4Q4
	PRDM12	ENST00000676323.1		c.906+168_906+170dupCGC		intron	N/A	ENSP00000502471.1	A0A6Q8PH01

Frequencies

GnomAD3 genomes

AF:

0.400

AC:

56728

AN:

141750

Hom.:

11863

Cov.:

show subpopulations

Gnomad AFR

AF:

0.470

Gnomad AMI

AF:

0.322

Gnomad AMR

AF:

0.480

Gnomad ASJ

AF:

0.268

Gnomad EAS

AF:

0.608

Gnomad SAS

AF:

0.463

Gnomad FIN

AF:

0.392

Gnomad MID

AF:

0.295

Gnomad NFE

AF:

0.330

Gnomad OTH

AF:

0.389

GnomAD2 exomes

AF:

0.00

AC:

AN:

AF XY:

0.00

Gnomad NFE exome

AF:

0.00

GnomAD4 exome

AF:

0.291

AC:

234747

AN:

807512

Hom.:

19887

Cov.:

AF XY:

0.290

AC XY:

108501

AN XY:

374572

show subpopulations

African (AFR)

AF:

0.416

AC:

6107

AN:

14696

American (AMR)

AF:

0.338

AC:

428

AN:

1266

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

1193

AN:

5176

East Asian (EAS)

AF:

0.402

AC:

1559

AN:

3880

South Asian (SAS)

AF:

0.378

AC:

6058

AN:

16040

European-Finnish (FIN)

AF:

0.0575

AC:

AN:

1426

Middle Eastern (MID)

AF:

0.216

AC:

343

AN:

1588

European-Non Finnish (NFE)

AF:

0.286

AC:

210752

AN:

736866

Other (OTH)

AF:

0.310

AC:

8225

AN:

26574

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

7893

15787

23680

31574

39467

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10378

20756

31134

41512

51890

<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:

0.400

AC:

56740

AN:

141788

Hom.:

11866

Cov.:

AF XY:

0.405

AC XY:

27848

AN XY:

68684

show subpopulations

African (AFR)

AF:

0.470

AC:

18445

AN:

39248

American (AMR)

AF:

0.480

AC:

6941

AN:

14452

Ashkenazi Jewish (ASJ)

AF:

0.268

AC:

898

AN:

3350

East Asian (EAS)

AF:

0.608

AC:

2840

AN:

4672

South Asian (SAS)

AF:

0.461

AC:

2121

AN:

4600

European-Finnish (FIN)

AF:

0.392

AC:

3060

AN:

7808

Middle Eastern (MID)

AF:

0.289

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.330

AC:

21314

AN:

64574

Other (OTH)

AF:

0.392

AC:

763

AN:

1944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1566

3132

4698

6264

7830

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

532

1064

1596

2128

2660

<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:

0.217

Hom.:

347

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Congenital insensitivity to pain-hypohidrosis syndrome (1)

not provided (1)

PRDM12-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.091

Mutation Taster

=82/18

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGCCGC

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