12-8921663-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004426.3(PHC1):c.369C>T(p.Pro123=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.702 in 1,612,636 control chromosomes in the GnomAD database, including 401,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (30799 hom., cov: 30)
  • Exomes 𝑓: 0.71 (370829 hom.)
• Consequence: PHC1 NM_004426.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 12-8921663-C-T is Benign according to our data. Variant chr12-8921663-C-T is described in ClinVar as [Benign]. Clinvar id is 1252581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHC1	NM_004426.3	c.369C>T	p.Pro123=	synonymous_variant	5/15	ENST00000544916.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHC1	ENST00000544916.6	c.369C>T	p.Pro123=	synonymous_variant	5/15	1	NM_004426.3	P1

Frequencies

GnomAD3 genomes AF: 0.624 AC: 94684 AN: 151800 Hom.: 30797 Cov.: 30

Gnomad AFR AF: 0.431

Gnomad AMI AF: 0.635

Gnomad AMR AF: 0.604

Gnomad ASJ AF: 0.803

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.832

Gnomad FIN AF: 0.665

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.706

Gnomad OTH AF: 0.650

GnomAD3 exomes AF: 0.694 AC: 174055 AN: 250648 Hom.: 61584 AF XY: 0.710 AC XY: 96156 AN XY: 135512

Gnomad AFR exome AF: 0.426

Gnomad AMR exome AF: 0.620

Gnomad ASJ exome AF: 0.799

Gnomad EAS exome AF: 0.721

Gnomad SAS exome AF: 0.831

Gnomad FIN exome AF: 0.664

Gnomad NFE exome AF: 0.709

Gnomad OTH exome AF: 0.726

GnomAD4 exome AF: 0.710 AC: 1036883 AN: 1460718 Hom.: 370829 Cov.: 36 AF XY: 0.715 AC XY: 519665 AN XY: 726756

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.619

Gnomad4 ASJ exome AF: 0.798

Gnomad4 EAS exome AF: 0.727

Gnomad4 SAS exome AF: 0.831

Gnomad4 FIN exome AF: 0.659

Gnomad4 NFE exome AF: 0.712

Gnomad4 OTH exome AF: 0.710

GnomAD4 genome AF: 0.623 AC: 94716 AN: 151918 Hom.: 30799 Cov.: 30 AF XY: 0.622 AC XY: 46207 AN XY: 74240

Gnomad4 AFR AF: 0.430

Gnomad4 AMR AF: 0.604

Gnomad4 ASJ AF: 0.803

Gnomad4 EAS AF: 0.724

Gnomad4 SAS AF: 0.831

Gnomad4 FIN AF: 0.665

Gnomad4 NFE AF: 0.706

Gnomad4 OTH AF: 0.649

Alfa AF: 0.672 Hom.: 15202

Bravo AF: 0.608

Asia WGS AF: 0.741 AC: 2577 AN: 3478

EpiCase AF: 0.718

EpiControl AF: 0.726

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly 11, primary, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	11
Dann	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs1805741; hg19: chr12-9074259; COSMIC: COSV70418235; COSMIC: COSV70418235;