12-8921663-C-T

Variant names:

• chr12-8921663-C-T
• rs1805741
• NM_004426.3:c.369C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004426.3(PHC1):​c.369C>T​(p.Pro123Pro) 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:3
• Conservation: PhyloP100: 1.02
• Publications: 20 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 -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 rank	MANE	Protein	UniProt
PHC1	NM_004426.3	c.369C>T	p.Pro123Pro	synonymous_variant	Exon 5 of 15	ENST00000544916.6	NP_004417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHC1	ENST00000544916.6	c.369C>T	p.Pro123Pro	synonymous_variant	Exon 5 of 15	1	NM_004426.3	ENSP00000437659.1

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

GnomAD2 exomes AF: 0.694 AC: 174055 AN: 250648 AF XY: 0.710

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 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

African (AFR) AF: 0.425 AC: 14194 AN: 33412

American (AMR) AF: 0.619 AC: 27594 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 20816 AN: 26094

East Asian (EAS) AF: 0.727 AC: 28853 AN: 39666

South Asian (SAS) AF: 0.831 AC: 71573 AN: 86178

European-Finnish (FIN) AF: 0.659 AC: 35189 AN: 53408

Middle Eastern (MID) AF: 0.763 AC: 4399 AN: 5764

European-Non Finnish (NFE) AF: 0.712 AC: 791454 AN: 1111280

Other (OTH) AF: 0.710 AC: 42811 AN: 60334

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

African (AFR) AF: 0.430 AC: 17820 AN: 41418

American (AMR) AF: 0.604 AC: 9225 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.803 AC: 2784 AN: 3466

East Asian (EAS) AF: 0.724 AC: 3734 AN: 5156

South Asian (SAS) AF: 0.831 AC: 3988 AN: 4800

European-Finnish (FIN) AF: 0.665 AC: 7018 AN: 10554

Middle Eastern (MID) AF: 0.779 AC: 229 AN: 294

European-Non Finnish (NFE) AF: 0.706 AC: 47969 AN: 67938

Other (OTH) AF: 0.649 AC: 1370 AN: 2110

Alfa AF: 0.669 Hom.: 15282

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Microcephaly 11, primary, autosomal recessive Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.61
PhyloP100		1.0
Mutation Taster		=279/21	polymorphism (auto)

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

Other links and lift over

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