chr4-761339-C-T

Position:

• chr4-761339-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006315.7(PCGF3):​c.523C>T​(p.Arg175Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,458,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PCGF3 NM_006315.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.36

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]

LOC124900163 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCGF3	NM_006315.7	c.523C>T	p.Arg175Cys	missense_variant	9/11	ENST00000362003.10	NP_006306.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCGF3	ENST00000362003.10	c.523C>T	p.Arg175Cys	missense_variant	9/11	5	NM_006315.7	ENSP00000354724.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1458584 Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 4 AN XY: 725158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000226

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2024

The c.523C>T (p.R175C) alteration is located in exon 9 (coding exon 6) of the PCGF3 gene. This alteration results from a C to T substitution at nucleotide position 523, causing the arginine (R) at amino acid position 175 to be replaced by a cysteine (C). 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	0.92
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	D;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.7	M;M
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Uncertain	0.50
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.86
MutPred		0.77		Loss of MoRF binding (P = 0.0399);Loss of MoRF binding (P = 0.0399);
MVP		0.86
MPC		2.2
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.84
gMVP		0.86

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: rs1318646361; hg19: chr4-755127;