Genetic Variant PRDM12:p.Ala353_Ala359del (chr9-130681605-TCGCCGCCGCCGCCGCCGCCGC-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3BS1_Supporting

The NM_021619.3(PRDM12):c.1056_1076delCGCCGCCGCCGCCGCCGCCGC(p.Ala353_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 0.000892 in 955,252 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00097 ( 1 hom. )

Consequence

PRDM12
NM_021619.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

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 -2 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_021619.3

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000973 (791/813336) while in subpopulation EAS AF = 0.00152 (6/3958). AF 95% confidence interval is 0.000954. There are 1 homozygotes in GnomAdExome4. There are 386 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1056_1076delCGCCGCCGCCGCCGCCGCCGC	p.Ala353_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.1056_1076delCGCCGCCGCCGCCGCCGCCGC	p.Ala353_Ala359del	disruptive_inframe_deletion	Exon 5 of 5	ENSP00000253008.2	Q9H4Q4
	PRDM12	ENST00000676323.1		c.906+150_906+170delCGCCGCCGCCGCCGCCGCCGC		intron	N/A	ENSP00000502471.1	A0A6Q8PH01

Frequencies

GnomAD3 genomes

AF:

0.000430

AC:

AN:

141876

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000536

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000277

Gnomad ASJ

AF:

0.000299

Gnomad EAS

AF:

0.000639

Gnomad SAS

AF:

0.000433

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000433

Gnomad OTH

AF:

0.00104

GnomAD4 exome

AF:

0.000973

AC:

791

AN:

813336

Hom.:

AF XY:

0.00102

AC XY:

386

AN XY:

377254

show subpopulations

African (AFR)

AF:

0.000405

AC:

AN:

14820

American (AMR)

AF:

0.000785

AC:

AN:

1274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5224

East Asian (EAS)

AF:

0.00152

AC:

AN:

3958

South Asian (SAS)

AF:

0.000555

AC:

AN:

16210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1430

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1600

European-Non Finnish (NFE)

AF:

0.00101

AC:

753

AN:

742056

Other (OTH)

AF:

0.000598

AC:

AN:

26764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.608

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<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:

0.000430

AC:

AN:

141916

Hom.:

Cov.:

AF XY:

0.000451

AC XY:

AN XY:

68754

show subpopulations

African (AFR)

AF:

0.000534

AC:

AN:

39292

American (AMR)

AF:

0.000276

AC:

AN:

14472

Ashkenazi Jewish (ASJ)

AF:

0.000299

AC:

AN:

3350

East Asian (EAS)

AF:

0.000641

AC:

AN:

4680

South Asian (SAS)

AF:

0.000434

AC:

AN:

4604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7820

Middle Eastern (MID)

AF:

0.00

AC:

AN:

266

European-Non Finnish (NFE)

AF:

0.000433

AC:

AN:

64610

Other (OTH)

AF:

0.00103

AC:

AN:

1946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:Uncertain significance

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=197/3

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-TCGC

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