12-8917770-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004426.3(PHC1):c.93T>A(p.Leu31=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,561,100 control chromosomes in the GnomAD database, including 401,041 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (34995 hom., cov: 30)
  • Exomes 𝑓: 0.72 (366046 hom.)
• Consequence: PHC1 NM_004426.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0380

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 12-8917770-T-A is Benign according to our data. Variant chr12-8917770-T-A is described in ClinVar as [Benign]. Clinvar id is 1271948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.038 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHC1	NM_004426.3	c.93T>A	p.Leu31=	synonymous_variant	2/15	ENST00000544916.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHC1	ENST00000544916.6	c.93T>A	p.Leu31=	synonymous_variant	2/15	1	NM_004426.3	P1

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102498 AN: 151758 Hom.: 34987 Cov.: 30

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.637

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.804

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.833

Gnomad FIN AF: 0.685

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.714

Gnomad OTH AF: 0.687

GnomAD3 exomes AF: 0.709 AC: 157941 AN: 222630 Hom.: 56551 AF XY: 0.721 AC XY: 87489 AN XY: 121278

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.618

Gnomad ASJ exome AF: 0.800

Gnomad EAS exome AF: 0.743

Gnomad SAS exome AF: 0.826

Gnomad FIN exome AF: 0.688

Gnomad NFE exome AF: 0.712

Gnomad OTH exome AF: 0.730

GnomAD4 exome AF: 0.719 AC: 1012923 AN: 1409224 Hom.: 366046 Cov.: 25 AF XY: 0.723 AC XY: 507856 AN XY: 702106

Gnomad4 AFR exome AF: 0.583

Gnomad4 AMR exome AF: 0.621

Gnomad4 ASJ exome AF: 0.800

Gnomad4 EAS exome AF: 0.745

Gnomad4 SAS exome AF: 0.829

Gnomad4 FIN exome AF: 0.683

Gnomad4 NFE exome AF: 0.716

Gnomad4 OTH exome AF: 0.724

GnomAD4 genome AF: 0.675 AC: 102545 AN: 151876 Hom.: 34995 Cov.: 30 AF XY: 0.674 AC XY: 49997 AN XY: 74222

Gnomad4 AFR AF: 0.589

Gnomad4 AMR AF: 0.625

Gnomad4 ASJ AF: 0.804

Gnomad4 EAS AF: 0.753

Gnomad4 SAS AF: 0.832

Gnomad4 FIN AF: 0.685

Gnomad4 NFE AF: 0.714

Gnomad4 OTH AF: 0.686

Alfa AF: 0.694 Hom.: 9677

Bravo AF: 0.665

Asia WGS AF: 0.763 AC: 2652 AN: 3478

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	-0.50
Cadd	Benign	4.4
Dann	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs4883198; hg19: chr12-9070366; COSMIC: COSV70417649; COSMIC: COSV70417649;