Genetic Variant PRDM12:p.Ala358_Ala359dup (chr9-130681605-T-TCGCCGC) – 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.1071_1076dupCGCCGC(p.Ala358_Ala359dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A359A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.043 ( 171 hom., cov: 0)

Exomes 𝑓: 0.033 ( 292 hom. )

Consequence

PRDM12
NM_021619.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

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-TCGCCGC is Benign according to our data. Variant chr9-130681605-T-TCGCCGC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0669 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.1071_1076dupCGCCGC	p.Ala358_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.1071_1076dupCGCCGC	p.Ala358_Ala359dup	disruptive_inframe_insertion	Exon 5 of 5	ENSP00000253008.2	Q9H4Q4
	PRDM12	ENST00000676323.1		c.906+165_906+170dupCGCCGC		intron	N/A	ENSP00000502471.1	A0A6Q8PH01

Frequencies

GnomAD3 genomes

AF:

0.0427

AC:

6052

AN:

141834

Hom.:

172

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0691

Gnomad AMI

AF:

0.00571

Gnomad AMR

AF:

0.0318

Gnomad ASJ

AF:

0.0128

Gnomad EAS

AF:

0.0309

Gnomad SAS

AF:

0.0232

Gnomad FIN

AF:

0.0199

Gnomad MID

AF:

0.0137

Gnomad NFE

AF:

0.0364

Gnomad OTH

AF:

0.0383

GnomAD4 exome

AF:

0.0327

AC:

26517

AN:

811666

Hom.:

292

Cov.:

AF XY:

0.0325

AC XY:

12245

AN XY:

376500

show subpopulations

African (AFR)

AF:

0.0666

AC:

985

AN:

14780

American (AMR)

AF:

0.0134

AC:

AN:

1266

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

AN:

5220

East Asian (EAS)

AF:

0.0261

AC:

103

AN:

3948

South Asian (SAS)

AF:

0.0227

AC:

368

AN:

16182

European-Finnish (FIN)

AF:

0.00490

AC:

AN:

1430

Middle Eastern (MID)

AF:

0.0232

AC:

AN:

1596

European-Non Finnish (NFE)

AF:

0.0326

AC:

24130

AN:

740538

Other (OTH)

AF:

0.0303

AC:

809

AN:

26706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

Heterozygous variant carriers

1088

2176

3263

4351

5439

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1252

2504

3756

5008

6260

<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:

0.0427

AC:

6055

AN:

141872

Hom.:

171

Cov.:

AF XY:

0.0410

AC XY:

2818

AN XY:

68726

show subpopulations

African (AFR)

AF:

0.0691

AC:

2712

AN:

39268

American (AMR)

AF:

0.0317

AC:

459

AN:

14464

Ashkenazi Jewish (ASJ)

AF:

0.0128

AC:

AN:

3350

East Asian (EAS)

AF:

0.0306

AC:

143

AN:

4676

South Asian (SAS)

AF:

0.0233

AC:

107

AN:

4602

European-Finnish (FIN)

AF:

0.0199

AC:

156

AN:

7820

Middle Eastern (MID)

AF:

0.0150

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.0364

AC:

2351

AN:

64604

Other (OTH)

AF:

0.0385

AC:

AN:

1946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

273

546

820

1093

1366

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0192

Hom.:

347

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Congenital insensitivity to pain-hypohidrosis syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.091

Mutation Taster

=82/18

polymorphism

(source)

Splicing

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

Publications

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9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGCCGCCGCCGC

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