chr12-8932993-C-T

Variant names:

• chr12-8932993-C-T
• rs202158376
• NM_004426.3:c.1536C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6_Very_Strong BP7

The NM_004426.3(PHC1):​c.1536C>T​(p.Ala512Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (2 hom., cov: 20)
  • Exomes 𝑓: 0.0014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PHC1 NM_004426.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.388
• Publications: 0 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-8932993-C-T is Benign according to our data. Variant chr12-8932993-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 436307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.388 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC1	NM_004426.3	c.1536C>T	p.Ala512Ala	synonymous_variant	Exon 8 of 15	ENST00000544916.6	NP_004417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHC1	ENST00000544916.6	c.1536C>T	p.Ala512Ala	synonymous_variant	Exon 8 of 15	1	NM_004426.3	ENSP00000437659.1

Frequencies

GnomAD3 genomes AF: 0.00926 AC: 1210 AN: 130674 Hom.: 2 Cov.: 20

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00452

Gnomad ASJ AF: 0.000309

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000273

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00340

Gnomad NFE AF: 0.000227

Gnomad OTH AF: 0.0130

GnomAD2 exomes AF: 0.00282 AC: 223 AN: 79076 AF XY: 0.00222

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.000348

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.000401

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00138 AC: 771 AN: 558116 Hom.: 0 Cov.: 6 AF XY: 0.00114 AC XY: 334 AN XY: 291880

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0341 AC: 534 AN: 15678

American (AMR) AF: 0.00186 AC: 57 AN: 30632

Ashkenazi Jewish (ASJ) AF: 0.000608 AC: 10 AN: 16446

East Asian (EAS) AF: 0.00 AC: 0 AN: 31720

South Asian (SAS) AF: 0.0000745 AC: 4 AN: 53696

European-Finnish (FIN) AF: 0.0000274 AC: 1 AN: 36482

Middle Eastern (MID) AF: 0.00258 AC: 6 AN: 2326

European-Non Finnish (NFE) AF: 0.000188 AC: 64 AN: 341248

Other (OTH) AF: 0.00318 AC: 95 AN: 29888

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00928 AC: 1214 AN: 130762 Hom.: 2 Cov.: 20 AF XY: 0.00906 AC XY: 560 AN XY: 61844

African (AFR) AF: 0.0327 AC: 1120 AN: 34254

American (AMR) AF: 0.00451 AC: 55 AN: 12188

Ashkenazi Jewish (ASJ) AF: 0.000309 AC: 1 AN: 3232

East Asian (EAS) AF: 0.00 AC: 0 AN: 4838

South Asian (SAS) AF: 0.000273 AC: 1 AN: 3662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8034

Middle Eastern (MID) AF: 0.00735 AC: 2 AN: 272

European-Non Finnish (NFE) AF: 0.000227 AC: 14 AN: 61800

Other (OTH) AF: 0.0129 AC: 21 AN: 1634

Alfa AF: 0.00719 Hom.: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

May 24, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	8.9
DANN	Benign	0.48
PhyloP100		0.39
Mutation Taster		=100/0	polymorphism

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: rs202158376; hg19: chr12-9085589;