5-123180296-G-T

Variant names:

• chr5-123180296-G-T
• rs879255278
• NM_001136239.4:c.1646G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001136239.4(PRDM6):​c.1646G>T​(p.Arg549Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R549Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PRDM6 NM_001136239.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-123180296-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 243049.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

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.1646G>T	p.Arg549Leu	missense	Exon 7 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.1646G>T	p.Arg549Leu	missense	Exon 7 of 8	ENSP00000384725.3	Q9NQX0-3
	PRDM6	ENST00000890813.1		c.1646G>T	p.Arg549Leu	missense	Exon 6 of 7	ENSP00000560872.1
	PRDM6	ENST00000427739.1	TSL:3	n.233G>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		9.6
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.1	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.77		Loss of disorder (P = 0.0354)
MVP		0.57
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.72
gMVP		0.76
Mutation Taster		=35/65	disease causing

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: rs879255278; hg19: chr5-122515990;