5-123090135-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001136239.4(PRDM6):c.121G>C(p.Ala41Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A41A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PRDM6 NM_001136239.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.737

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08297169).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRDM6	NM_001136239.4	c.121G>C	p.Ala41Pro	missense_variant	2/8	ENST00000407847.5
PRDM6-AS1	NR_146771.1	n.182C>G		non_coding_transcript_exon_variant	1/2
PRDM6	XM_047417878.1	c.121G>C	p.Ala41Pro	missense_variant	2/4
PRDM6	XR_001742346.2	n.415G>C		non_coding_transcript_exon_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRDM6	ENST00000407847.5	c.121G>C	p.Ala41Pro	missense_variant	2/8	5	NM_001136239.4	P1
PRDM6-AS1	ENST00000458103.2	n.165C>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000144 AC: 2 AN: 1385354 Hom.: 0 Cov.: 31 AF XY: 0.00000293 AC XY: 2 AN XY: 683406

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2022

The c.121G>C (p.A41P) alteration is located in exon 2 (coding exon 1) of the PRDM6 gene. This alteration results from a G to C substitution at nucleotide position 121, causing the alanine (A) at amino acid position 41 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	7.7
Dann	Benign	0.91
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.048
Sift	Benign	0.032	D
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.33
MutPred		0.15		Gain of loop (P = 0.024);
MVP		0.055
ClinPred		0.071	T
GERP RS		0.54
Varity_R		0.12
gMVP		0.24

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: rs1218441375; hg19: chr5-122425830;