12-8932728-CGCAGCAGCA-CGCAGCAGCAGCAGCAGCA

Variant names:

• chr12-8932728-C-CGCAGCAGCA
• rs368945524
• NM_004426.3:c.1281_1289dupGCAGCAGCA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_004426.3(PHC1):​c.1281_1289dupGCAGCAGCA​(p.Gln428_Gln430dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PHC1 NM_004426.3 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.299
• Publications: 2 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004426.3.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHC1	NM_004426.3	MANE Select	c.1281_1289dupGCAGCAGCA	p.Gln428_Gln430dup	disruptive_inframe_insertion	Exon 8 of 15	NP_004417.2
	PHC1	NM_001413738.1		c.1281_1289dupGCAGCAGCA	p.Gln428_Gln430dup	disruptive_inframe_insertion	Exon 8 of 15	NP_001400667.1
	PHC1	NM_001413739.1		c.1275_1283dupGCAGCAGCA	p.Gln426_Gln428dup	disruptive_inframe_insertion	Exon 8 of 15	NP_001400668.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHC1	ENST00000544916.6	TSL:1 MANE Select	c.1281_1289dupGCAGCAGCA	p.Gln428_Gln430dup	disruptive_inframe_insertion	Exon 8 of 15	ENSP00000437659.1
	PHC1	ENST00000543824.5	TSL:1	c.1281_1289dupGCAGCAGCA	p.Gln428_Gln430dup	disruptive_inframe_insertion	Exon 9 of 16	ENSP00000440674.1
	PHC1	ENST00000433083.6	TSL:1	c.1146_1154dupGCAGCAGCA	p.Gln383_Gln385dup	disruptive_inframe_insertion	Exon 7 of 14	ENSP00000399194.2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000137 AC: 2 AN: 1461032 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726800

⚠️ 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: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111274

Other (OTH) AF: 0.00 AC: 0 AN: 60358

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000983081), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 27

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.30
Mutation Taster		=71/29	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs368945524; hg19: chr12-9085324;