12-8922698-A-C

Position:

• chr12-8922698-A-C

Variant summary

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

The NM_004426.3(PHC1):​c.522A>C​(p.Gln174His) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHC1 NM_004426.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.242

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=0.30646583).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHC1	NM_004426.3	c.522A>C	p.Gln174His	missense_variant	6/15	ENST00000544916.6	NP_004417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHC1	ENST00000544916.6	c.522A>C	p.Gln174His	missense_variant	6/15	1	NM_004426.3	ENSP00000437659.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Aug 12, 2024

The c.522A>C (p.Q174H) alteration is located in exon 6 (coding exon 5) of the PHC1 gene. This alteration results from a A to C substitution at nucleotide position 522, causing the glutamine (Q) at amino acid position 174 to be replaced by a histidine (H). 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	0.73
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;T;T;.
Eigen	Benign	-0.050
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.96	.;D;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.6	L;.;L;.;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-1.2	N;N;N;N;D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D
Polyphen		1.0	D;.;D;.;.
Vest4		0.80
MutPred		0.42		Gain of catalytic residue at V169 (P = 0.0039);.;Gain of catalytic residue at V169 (P = 0.0039);.;.;
MVP		0.47
MPC		1.8
ClinPred		0.97	D
GERP RS		-6.1
Varity_R		0.50
gMVP		0.89

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: rs200633434; hg19: chr12-9075294;