4-733716-C-A

Variant names:

• chr4-733716-C-A
• rs372489853
• NM_006315.7:c.36C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006315.7(PCGF3):​c.36C>A​(p.Asn12Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,442 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PCGF3 NM_006315.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0420

Genes affected

PCGF3 (HGNC:10066): (polycomb group ring finger 3) The protein encoded by this gene contains a C3HC4 type RING finger, which is a motif known to be involved in protein-protein interactions. The specific function of this protein has not yet been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCGF3	NM_006315.7	c.36C>A	p.Asn12Lys	missense_variant	Exon 4 of 11	ENST00000362003.10	NP_006306.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCGF3	ENST00000362003.10	c.36C>A	p.Asn12Lys	missense_variant	Exon 4 of 11	5	NM_006315.7	ENSP00000354724.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246234 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133806

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458442 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725696

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.36C>A (p.N12K) alteration is located in exon 4 (coding exon 1) of the PCGF3 gene. This alteration results from a C to A substitution at nucleotide position 36, causing the asparagine (N) at amino acid position 12 to be replaced by a lysine (K). 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	Pathogenic	1.0
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	.;D;D;.;D;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D;.;D;D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.0	.;M;.;.;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.0	D;D;D;D;D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;T;D;D
Polyphen		1.0	.;D;.;.;D;.
Vest4		0.92, 0.62, 0.92
MutPred		0.54		Loss of ubiquitination at K7 (P = 0.0435);Loss of ubiquitination at K7 (P = 0.0435);Loss of ubiquitination at K7 (P = 0.0435);Loss of ubiquitination at K7 (P = 0.0435);Loss of ubiquitination at K7 (P = 0.0435);Loss of ubiquitination at K7 (P = 0.0435);
MVP		0.73
MPC		2.1
ClinPred		0.99	D
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.94

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: rs372489853; hg19: chr4-727505;