rs4883201

Variant names:

• chr12-8929985-A-G
• rs4883201
• NM_004426.3:c.613-450A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004426.3(PHC1):​c.613-450A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0906 in 152,096 control chromosomes in the GnomAD database, including 901 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.091 (901 hom., cov: 31)
• Consequence: PHC1 NM_004426.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.712
• Publications: 47 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC1	NM_004426.3	c.613-450A>G		intron_variant	Intron 6 of 14	ENST00000544916.6	NP_004417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHC1	ENST00000544916.6	c.613-450A>G		intron_variant	Intron 6 of 14	1	NM_004426.3	ENSP00000437659.1

Frequencies

GnomAD3 genomes AF: 0.0907 AC: 13792 AN: 151978 Hom.: 905 Cov.: 31

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.0779

Gnomad ASJ AF: 0.120

Gnomad EAS AF: 0.311

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.107

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0906 AC: 13782 AN: 152096 Hom.: 901 Cov.: 31 AF XY: 0.0951 AC XY: 7070 AN XY: 74348

African (AFR) AF: 0.0199 AC: 824 AN: 41506

American (AMR) AF: 0.0778 AC: 1187 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 418 AN: 3472

East Asian (EAS) AF: 0.312 AC: 1607 AN: 5158

South Asian (SAS) AF: 0.222 AC: 1068 AN: 4810

European-Finnish (FIN) AF: 0.118 AC: 1248 AN: 10574

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 7032 AN: 67992

Other (OTH) AF: 0.106 AC: 225 AN: 2116

Alfa AF: 0.104 Hom.: 2444

Bravo AF: 0.0822

Asia WGS AF: 0.242 AC: 838 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.41
DANN	Benign	0.68
PhyloP100		-0.71
Mutation Taster		=100/0	polymorphism (auto)

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: rs4883201; hg19: chr12-9082581;