12-8921058-A-C

Variant names:

• chr12-8921058-A-C
• rs139679067
• NM_004426.3:c.299A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004426.3(PHC1):​c.299A>C​(p.Gln100Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHC1 NM_004426.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.10

Genes affected

PHC1 (HGNC:3182): (polyhomeotic homolog 1) This gene is a homolog of the Drosophila polyhomeotic gene, which is a member of the Polycomb group of genes. The gene product is a component of a multimeric protein complex that contains EDR2 and the vertebrate Polycomb protein BMH1. The gene product, the EDR2 protein, and the Drosophila polyhomeotic protein share 2 highly conserved domains, named homology domains I and II. These domains are involved in protein-protein interactions and may mediate heterodimerization of the protein encoded by this gene and the EDR2 protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38515112).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC1	NM_004426.3	c.299A>C	p.Gln100Pro	missense_variant	Exon 4 of 15	ENST00000544916.6	NP_004417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHC1	ENST00000544916.6	c.299A>C	p.Gln100Pro	missense_variant	Exon 4 of 15	1	NM_004426.3	ENSP00000437659.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.082	T;T;T;T;T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;.;T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.39	T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.97	.;L;.;L;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.0	D;N;N;N;D;N;D
REVEL	Benign	0.10
Sift	Uncertain	0.014	D;D;D;D;D;D;D
Sift4G	Benign	0.10	T;T;T;T;T;T;T
Polyphen		0.97	.;D;.;D;.;.;.
Vest4		0.56, 0.46
MutPred		0.19		Gain of catalytic residue at L105 (P = 0.0095);Gain of catalytic residue at L105 (P = 0.0095);.;Gain of catalytic residue at L105 (P = 0.0095);Gain of catalytic residue at L105 (P = 0.0095);Gain of catalytic residue at L105 (P = 0.0095);.;
MVP		0.43
MPC		1.8
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.71
gMVP		0.62

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: rs139679067; hg19: chr12-9073654;