12-8930738-A-C

Variant names:

• chr12-8930738-A-C
• NM_004426.3:c.916A>C
• PHC1 p.Arg306Arg

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_004426.3(PHC1):​c.916A>C​(p.Arg306Arg) variant causes a synonymous 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R306R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 25)
• Consequence: PHC1 NM_004426.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004426.3. 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
	PHC1	NM_004426.3	MANE Select	c.916A>C	p.Arg306Arg	synonymous	Exon 7 of 15	NP_004417.2	P78364
	PHC1	NM_001413738.1		c.916A>C	p.Arg306Arg	synonymous	Exon 7 of 15	NP_001400667.1	P78364
	PHC1	NM_001413739.1		c.910A>C	p.Arg304Arg	synonymous	Exon 7 of 15	NP_001400668.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHC1	ENST00000544916.6	TSL:1 MANE Select	c.916A>C	p.Arg306Arg	synonymous	Exon 7 of 15	ENSP00000437659.1	P78364
	PHC1	ENST00000543824.5	TSL:1	c.916A>C	p.Arg306Arg	synonymous	Exon 8 of 16	ENSP00000440674.1	P78364
	PHC1	ENST00000433083.6	TSL:1	c.781A>C	p.Arg261Arg	synonymous	Exon 6 of 14	ENSP00000399194.2	J3KQH6

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 17

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	10
DANN	Benign	0.61
PhyloP100		1.1
PromoterAI		0.0038	Neutral

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-9083334;