Genetic Variant PRDM6:p.Pro58AlafsTer6 (chr5-123090181-C-CG) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_001136239.4(PRDM6):c.167_168insG(p.Pro58AlafsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,487,364 control chromosomes in the GnomAD database, including 53 homozygotes. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P56P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.011 ( 32 hom., cov: 33)

Exomes 𝑓: 0.00091 ( 21 hom. )

Consequence

PRDM6
NM_001136239.4 frameshift

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -2.59

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 made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP6

Variant 5-123090181-C-CG is Benign according to our data. Variant chr5-123090181-C-CG is described in ClinVar as [Benign]. Clinvar id is 768029.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0111 (1692/151936) while in subpopulation AFR AF= 0.0387 (1608/41498). AF 95% confidence interval is 0.0372. There are 32 homozygotes in gnomad4. There are 768 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1692 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRDM6	NM_001136239.4 link	c.167_168insG	p.Pro58AlafsTer6	frameshift_variant	Exon 2 of 8	ENST00000407847.5	NP_001129711.1	Q9NQX0-3
PRDM6	XM_047417878.1 link	c.167_168insG	p.Pro58AlafsTer6	frameshift_variant	Exon 2 of 4		XP_047273834.1
PRDM6-AS1	NR_146771.1 link	n.135_136insC		non_coding_transcript_exon_variant	Exon 1 of 2
PRDM6	XR_001742346.2 link	n.461_462insG		non_coding_transcript_exon_variant	Exon 2 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRDM6	ENST00000407847.5 link	c.167_168insG	p.Pro58AlafsTer6	frameshift_variant	Exon 2 of 8	5	NM_001136239.4	ENSP00000384725.3		Q9NQX0-3
PRDM6-AS1	ENST00000458103.2 link	n.118_119insC		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1693

AN:

151828

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0389

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00387

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.00912

GnomAD3 exomes

AF:

0.000119

AC:

AN:

84056

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

47666

show subpopulations

Gnomad AFR exome

AF:

0.00797

Gnomad AMR exome

AF:

0.000133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000427

GnomAD4 exome

AF:

0.000914

AC:

1220

AN:

1335428

Hom.:

Cov.:

AF XY:

0.000784

AC XY:

516

AN XY:

658028

show subpopulations

Gnomad4 AFR exome

AF:

0.0389

Gnomad4 AMR exome

AF:

0.00141

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000692

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000313

Gnomad4 OTH exome

AF:

0.00205

GnomAD4 genome

AF:

0.0111

AC:

1692

AN:

151936

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

768

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.0387

Gnomad4 AMR

AF:

0.00387

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.00902

Alfa

AF:

0.000283

Hom.:

Asia WGS

AF:

0.000291

AC:

AN:

3450

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PRDM6-related disorder

Benign:1

Sep 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over