12-8921662-C-T

Variant names:

• chr12-8921662-C-T
• NM_004426.3:c.368C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004426.3(PHC1):​c.368C>T​(p.Pro123Leu) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P123S) has been classified 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: 3.80
• Publications: 0 publications found

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]

PHC1 Gene-Disease associations (from GenCC):

• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microcephaly 11, primary, autosomal recessive

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26168966).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC1	NM_004426.3	c.368C>T	p.Pro123Leu	missense_variant	Exon 5 of 15	ENST00000544916.6	NP_004417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHC1	ENST00000544916.6	c.368C>T	p.Pro123Leu	missense_variant	Exon 5 of 15	1	NM_004426.3	ENSP00000437659.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000611 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.368C>T (p.P123L) alteration is located in exon 5 (coding exon 4) of the PHC1 gene. This alteration results from a C to T substitution at nucleotide position 368, causing the proline (P) at amino acid position 123 to be replaced by a leucine (L). 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	Benign	0.33
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T;T;T;T;T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	.;N;.;N;.;.
PhyloP100		3.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.5	N;N;N;N;N;D
REVEL	Benign	0.17
Sift	Uncertain	0.019	D;D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D
Polyphen		0.99	.;D;.;D;.;.
Vest4		0.53, 0.54, 0.52
MutPred		0.23		Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);.;Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);.;
MVP		0.19
MPC		1.7
ClinPred		0.88	D
GERP RS		5.6
Varity_R		0.23
gMVP		0.63
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr12-9074258;