NM_006315.7:c.461A>G

Variant names:

• chr4-744687-A-G
• NM_006315.7:c.461A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006315.7(PCGF3):​c.461A>G​(p.Gln154Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCGF3 NM_006315.7 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.81
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006315.7. 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
	PCGF3	NM_006315.7	MANE Select	c.461A>G	p.Gln154Arg	missense splice_region	Exon 8 of 11	NP_006306.2
	PCGF3	NM_001317836.3		c.461A>G	p.Gln154Arg	missense splice_region	Exon 9 of 12	NP_001304765.1	Q3KNV8-1
	PCGF3	NM_001395245.1		c.461A>G	p.Gln154Arg	missense splice_region	Exon 9 of 12	NP_001382174.1	Q3KNV8-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCGF3	ENST00000362003.10	TSL:5 MANE Select	c.461A>G	p.Gln154Arg	missense splice_region	Exon 8 of 11	ENSP00000354724.5	Q3KNV8-1
	PCGF3	ENST00000470161.6	TSL:1	c.461A>G	p.Gln154Arg	missense splice_region	Exon 8 of 11	ENSP00000420489.2	Q3KNV8-1
	PCGF3	ENST00000870362.1		c.461A>G	p.Gln154Arg	missense splice_region	Exon 9 of 12	ENSP00000540421.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000360 AC: 5 AN: 1388940 Hom.: 0 Cov.: 30 AF XY: 0.00000584 AC XY: 4 AN XY: 685000

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30972

American (AMR) AF: 0.00 AC: 0 AN: 35614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24712

East Asian (EAS) AF: 0.00 AC: 0 AN: 35672

South Asian (SAS) AF: 0.00 AC: 0 AN: 78074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4948

European-Non Finnish (NFE) AF: 0.00000373 AC: 4 AN: 1073644

Other (OTH) AF: 0.0000174 AC: 1 AN: 57352

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.8
PrimateAI	Pathogenic	0.80	D
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.45
MutPred		0.29		Gain of glycosylation at S151 (P = 0.0135)
MVP		0.69
MPC		1.9
ClinPred		0.98	D
GERP RS		4.4
Varity_R		0.57
gMVP		0.78
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.37		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr4-738475;