dbSNP rs1429038624: PRDM12:p.Ala348_Ala349insThr (chr9-130681607-G-GCCA) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3BS1

The NM_021619.3(PRDM12):c.1044_1045insACC(p.Ala348_Ala349insThr) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 662,116 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000056 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

PRDM12
NM_021619.3 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 0.595

Publications

0 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 -5 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_021619.3

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000564 (7/124006) while in subpopulation EAS AF = 0.00237 (7/2952). AF 95% confidence interval is 0.00111. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 30. 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.1044_1045insACC	p.Ala348_Ala349insThr	conservative_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.1044_1045insACC	p.Ala348_Ala349insThr	conservative_inframe_insertion	Exon 5 of 5	ENSP00000253008.2	Q9H4Q4
	PRDM12	ENST00000676323.1		c.906+138_906+139insACC		intron	N/A	ENSP00000502471.1	A0A6Q8PH01

Frequencies

GnomAD3 genomes

AF:

0.0000565

AC:

AN:

123948

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00237

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000167

AC:

AN:

538110

Hom.:

Cov.:

AF XY:

0.0000121

AC XY:

AN XY:

248358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

11376

American (AMR)

AF:

0.00

AC:

AN:

700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3060

East Asian (EAS)

AF:

0.00444

AC:

AN:

1800

South Asian (SAS)

AF:

0.00

AC:

AN:

11094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

210

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1080

European-Non Finnish (NFE)

AF:

0.00000203

AC:

AN:

491416

Other (OTH)

AF:

0.00

AC:

AN:

17374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000564

AC:

AN:

124006

Hom.:

Cov.:

AF XY:

0.0000996

AC XY:

AN XY:

60212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

37524

American (AMR)

AF:

0.00

AC:

AN:

11968

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2582

East Asian (EAS)

AF:

0.00237

AC:

AN:

2952

South Asian (SAS)

AF:

0.00

AC:

AN:

3914

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7194

Middle Eastern (MID)

AF:

0.00

AC:

AN:

244

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

55068

Other (OTH)

AF:

0.00

AC:

AN:

1680

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

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.:

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

0.59

Mutation Taster

=80/20

polymorphism

(source)

Splicing

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

Publications

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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