Genetic Variant PRDM6:p.Pro58_Pro59dup (chr5-123090176-G-GCCGCCC) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4BS2

The NM_001136239.4(PRDM6):c.172_177dupCCCCCG(p.Pro58_Pro59dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000454 in 1,487,526 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00062 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00044 ( 7 hom. )

Consequence

PRDM6
NM_001136239.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.544

Publications

0 publications found

Variant links:

Genes affected

PRDM6 (HGNC:9350): (PR/SET domain 6) The protein encoded by this gene is a transcriptional repressor and a member of the PRDM family. Family members contain a PR domain and multiple zinc-finger domains. The encoded protein is involved in regulation of vascular smooth muscle cells (VSMC) contractile proteins. Mutations in this gene result in patent ductus arteriosus 3 (PDA3). [provided by RefSeq, Apr 2017]

PRDM6 links:

PRDM6-AS1 (HGNC:55869): (PRDM6 antisense RNA 1)

PRDM6-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001136239.4.

BS2

High AC in GnomAd4 at 94 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136239.4. 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
	PRDM6	NM_001136239.4	MANE Select	c.172_177dupCCCCCG	p.Pro58_Pro59dup	conservative_inframe_insertion	Exon 2 of 8	NP_001129711.1	Q9NQX0-3
	PRDM6-AS1	NR_146771.1		n.135_140dupGGGCGG		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PRDM6	ENST00000407847.5	TSL:5 MANE Select	c.172_177dupCCCCCG	p.Pro58_Pro59dup	conservative_inframe_insertion	Exon 2 of 8	ENSP00000384725.3	Q9NQX0-3
PRDM6	ENST00000890813.1		c.172_177dupCCCCCG	p.Pro58_Pro59dup	conservative_inframe_insertion	Exon 1 of 7	ENSP00000560872.1
PRDM6-AS1	ENST00000458103.3	TSL:2	n.118_123dupGGGCGG		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.000619

AC:

AN:

151862

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.00788

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000349

AC:

AN:

83104

AF XY:

0.000444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000678

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000651

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000434

GnomAD4 exome

AF:

0.000436

AC:

582

AN:

1335556

Hom.:

Cov.:

AF XY:

0.000530

AC XY:

349

AN XY:

658096

show subpopulations

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

African (AFR)

AF:

0.000868

AC:

AN:

26488

American (AMR)

AF:

0.0000740

AC:

AN:

27012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22786

East Asian (EAS)

AF:

0.000553

AC:

AN:

28958

South Asian (SAS)

AF:

0.00463

AC:

334

AN:

72102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4294

European-Non Finnish (NFE)

AF:

0.000153

AC:

161

AN:

1054706

Other (OTH)

AF:

0.000835

AC:

AN:

55108

⚠️ 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: 0.331

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000619

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.000767

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.000795

AC:

AN:

41506

American (AMR)

AF:

0.000196

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00175

AC:

AN:

5150

South Asian (SAS)

AF:

0.00789

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67922

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000855

Hom.:

Asia WGS

AF:

0.00553

AC:

AN:

3450

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial patent arterial duct (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.54

Mutation Taster

=69/31

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