Genetic Variant PRDM12:p.Ala359del (chr9-130681605-TCGC-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS1

The NM_021619.3(PRDM12):c.1074_1076delCGC(p.Ala359del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 942,186 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00078 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0016 ( 0 hom. )

Consequence

PRDM12
NM_021619.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.33

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: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_021619.3

BP6

Variant 9-130681605-TCGC-T is Benign according to our data. Variant chr9-130681605-TCGC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 648392.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000775 (110/141916) while in subpopulation AFR AF = 0.00211 (83/39292). AF 95% confidence interval is 0.00175. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 0. 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.1074_1076delCGC	p.Ala359del	disruptive_inframe_deletion	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_1076delCGC	p.Ala359del	disruptive_inframe_deletion	Exon 5 of 5	ENSP00000253008.2	Q9H4Q4
	PRDM12	ENST00000676323.1		c.906+168_906+170delCGC		intron	N/A	ENSP00000502471.1	A0A6Q8PH01

Frequencies

GnomAD3 genomes

AF:

0.000768

AC:

109

AN:

141876

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00209

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00107

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000256

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000248

Gnomad OTH

AF:

0.00104

GnomAD2 exomes

AF:

0.00

AC:

AN:

AF XY:

0.00

Gnomad NFE exome

AF:

0.00

GnomAD4 exome

AF:

0.00160

AC:

1281

AN:

800270

Hom.:

AF XY:

0.00162

AC XY:

601

AN XY:

371246

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00369

AC:

AN:

14644

American (AMR)

AF:

0.00158

AC:

AN:

1266

Ashkenazi Jewish (ASJ)

AF:

0.00137

AC:

AN:

5126

East Asian (EAS)

AF:

0.00203

AC:

AN:

3950

South Asian (SAS)

AF:

0.000936

AC:

AN:

16028

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1428

Middle Eastern (MID)

AF:

0.000643

AC:

AN:

1556

European-Non Finnish (NFE)

AF:

0.00159

AC:

1159

AN:

729900

Other (OTH)

AF:

0.00133

AC:

AN:

26372

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.281

Heterozygous variant carriers

187

375

562

750

937

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

116

174

232

290

<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:

0.000775

AC:

110

AN:

141916

Hom.:

Cov.:

AF XY:

0.000814

AC XY:

AN XY:

68754

show subpopulations

African (AFR)

AF:

0.00211

AC:

AN:

39292

American (AMR)

AF:

0.000138

AC:

AN:

14472

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3350

East Asian (EAS)

AF:

0.00107

AC:

AN:

4680

South Asian (SAS)

AF:

0.00

AC:

AN:

4604

European-Finnish (FIN)

AF:

0.000256

AC:

AN:

7820

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.000248

AC:

AN:

64610

Other (OTH)

AF:

0.00103

AC:

AN:

1946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

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:

0.00

Hom.:

347

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital insensitivity to pain-hypohidrosis syndrome (1)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=93/7

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.

9-130681605-TCGCCGCCGCCGCCGCCGCCGCCGC-TCGCCGCCGCCGCCGCCGCCGC

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