5-123090137-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001136239.4(PRDM6):c.123G>T(p.Ala41=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 1,534,948 control chromosomes in the GnomAD database, including 94,767 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (8101 hom., cov: 32)
  • Exomes 𝑓: 0.35 (86666 hom.)
• Consequence: PRDM6 NM_001136239.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.260

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

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 5-123090137-G-T is Benign according to our data. Variant chr5-123090137-G-T is described in ClinVar as [Benign]. Clinvar id is 3060736.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.26 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM6	NM_001136239.4	c.123G>T	p.Ala41=	synonymous_variant	2/8	ENST00000407847.5
PRDM6-AS1	NR_146771.1	n.180C>A		non_coding_transcript_exon_variant	1/2
PRDM6	XM_047417878.1	c.123G>T	p.Ala41=	synonymous_variant	2/4
PRDM6	XR_001742346.2	n.417G>T		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM6	ENST00000407847.5	c.123G>T	p.Ala41=	synonymous_variant	2/8	5	NM_001136239.4	P1
PRDM6-AS1	ENST00000458103.2	n.163C>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48364 AN: 151674 Hom.: 8092 Cov.: 32

Gnomad AFR AF: 0.285

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.0334

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.293

Gnomad MID AF: 0.398

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.358

GnomAD3 exomes AF: 0.287 AC: 35898 AN: 125114 Hom.: 5926 AF XY: 0.282 AC XY: 19368 AN XY: 68722

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.274

Gnomad ASJ exome AF: 0.345

Gnomad EAS exome AF: 0.0310

Gnomad SAS exome AF: 0.173

Gnomad FIN exome AF: 0.290

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.346 AC: 478104 AN: 1383166 Hom.: 86666 Cov.: 47 AF XY: 0.340 AC XY: 232127 AN XY: 682320

Gnomad4 AFR exome AF: 0.290

Gnomad4 AMR exome AF: 0.281

Gnomad4 ASJ exome AF: 0.346

Gnomad4 EAS exome AF: 0.0332

Gnomad4 SAS exome AF: 0.170

Gnomad4 FIN exome AF: 0.299

Gnomad4 NFE exome AF: 0.375

Gnomad4 OTH exome AF: 0.329

GnomAD4 genome AF: 0.319 AC: 48410 AN: 151782 Hom.: 8101 Cov.: 32 AF XY: 0.309 AC XY: 22921 AN XY: 74192

Gnomad4 AFR AF: 0.285

Gnomad4 AMR AF: 0.322

Gnomad4 ASJ AF: 0.350

Gnomad4 EAS AF: 0.0333

Gnomad4 SAS AF: 0.155

Gnomad4 FIN AF: 0.293

Gnomad4 NFE AF: 0.372

Gnomad4 OTH AF: 0.361

Alfa AF: 0.253 Hom.: 1001

Bravo AF: 0.322

Asia WGS AF: 0.142 AC: 495 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PRDM6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2020

This variant is classified as 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
BayesDel_noAF	Benign	-0.77
Cadd	Benign	6.0
Dann	Benign	0.68

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

Other links and lift over

dbSNP: rs13182369; hg19: chr5-122425832; COSMIC: COSV68335768; COSMIC: COSV68335768;