rs587777036

Variant names:

• chr12-8939418-C-T
• rs587777036
• NM_004426.3:c.2974C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_004426.3(PHC1):​c.2974C>T​(p.Leu992Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 29)
• Consequence: PHC1 NM_004426.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 7.91
• Publications: 5 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.859
• PP5: Variant 12-8939418-C-T is Pathogenic according to our data. Variant chr12-8939418-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 65406.Status of the report is no_assertion_criteria_provided, 0 stars.

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.2974C>T	p.Leu992Phe	missense	Exon 15 of 15	NP_004417.2	P78364
	PHC1	NM_001413738.1		c.2974C>T	p.Leu992Phe	missense	Exon 15 of 15	NP_001400667.1	P78364
	PHC1	NM_001413739.1		c.2968C>T	p.Leu990Phe	missense	Exon 15 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.2974C>T	p.Leu992Phe	missense	Exon 15 of 15	ENSP00000437659.1	P78364
	PHC1	ENST00000543824.5	TSL:1	c.2974C>T	p.Leu992Phe	missense	Exon 16 of 16	ENSP00000440674.1	P78364
	PHC1	ENST00000433083.6	TSL:1	c.2839C>T	p.Leu947Phe	missense	Exon 14 of 14	ENSP00000399194.2	J3KQH6

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 29

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Microcephaly 11, primary, autosomal recessive (1)
1	-	-	Primary microcephaly;C3714756:Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.64		Gain of catalytic residue at G989 (P = 0.0026)
MVP		0.38
MPC		1.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.73
gMVP		0.53
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777036; hg19: chr12-9092014;