Genetic Variant PRDM6:p.Pro58Leu (chr5-123090187-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001136239.4(PRDM6):c.173C>T(p.Pro58Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 1,488,140 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P58R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

PRDM6
NM_001136239.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.63

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0743857).

BS2

High AC in GnomAd4 at 6 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.173C>T	p.Pro58Leu	missense	Exon 2 of 8	NP_001129711.1	Q9NQX0-3
	PRDM6-AS1	NR_146771.1		n.130G>A		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.173C>T	p.Pro58Leu	missense	Exon 2 of 8	ENSP00000384725.3	Q9NQX0-3
PRDM6	ENST00000890813.1		c.173C>T	p.Pro58Leu	missense	Exon 1 of 7	ENSP00000560872.1
PRDM6-AS1	ENST00000458103.3	TSL:2	n.113G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000776

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000118

AC:

AN:

84920

AF XY:

0.0000207

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000309

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000105

AC:

AN:

1336298

Hom.:

Cov.:

AF XY:

0.0000106

AC XY:

AN XY:

658596

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26576

American (AMR)

AF:

0.00

AC:

AN:

27532

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22980

East Asian (EAS)

AF:

0.0000347

AC:

AN:

28848

South Asian (SAS)

AF:

0.00

AC:

AN:

72578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4288

European-Non Finnish (NFE)

AF:

0.0000114

AC:

AN:

1054706

Other (OTH)

AF:

0.0000181

AC:

AN:

55136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.0000395

AC:

AN:

151842

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.0000656

AC:

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000776

AC:

AN:

5154

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10518

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67924

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

Bravo

AF:

0.0000151

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.00049

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.43

M_CAP

Benign

0.040

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.46

PhyloP100

2.6

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

0.23

REVEL

Benign

0.082

Sift

Benign

0.32

Sift4G

Benign

0.083

Polyphen

0.14

Vest4

0.32

MutPred

0.24

Loss of glycosylation at P58 (P = 0.0017)

MVP

0.32

ClinPred

0.31

GERP RS

2.8

Varity_R

0.051

gMVP

0.41

Mutation Taster

=84/16

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

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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