rs879253872

Variant names:

• chr5-123170997-A-G
• rs879253872
• NM_001136239.4:c.1385A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001136239.4(PRDM6):​c.1385A>G​(p.Gln462Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,399,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q462H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: PRDM6 NM_001136239.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.26
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• familial patent arterial duct

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• patent ductus arteriosus 3

  Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-123170997-A-G is Pathogenic according to our data. Variant chr5-123170997-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 243051.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1385A>G	p.Gln462Arg	missense	Exon 6 of 8	NP_001129711.1	Q9NQX0-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PRDM6	ENST00000407847.5	TSL:5 MANE Select	c.1385A>G	p.Gln462Arg	missense	Exon 6 of 8	ENSP00000384725.3	Q9NQX0-3
	PRDM6	ENST00000890813.1		c.1385A>G	p.Gln462Arg	missense	Exon 5 of 7	ENSP00000560872.1
	PRDM6	ENST00000434521.1	TSL:2	n.*229A>G		non_coding_transcript_exon	Exon 2 of 3	ENSP00000390919.1	H7BZR2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000638 AC: 1 AN: 156804 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000165

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1399576 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690288

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1079020

Other (OTH) AF: 0.0000172 AC: 1 AN: 58050

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Patent ductus arteriosus 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.00084	T
Eigen	Uncertain	0.64
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		9.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.39
Sift	Benign	0.055	T
Sift4G	Benign	0.65	T
Polyphen		0.99	D
Vest4		0.89
MutPred		0.18		Gain of phosphorylation at T460 (P = 0.0962)
MVP		0.49
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.42
gMVP		0.47
Mutation Taster		=22/78	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs879253872; hg19: chr5-122506691;