12-8932728-CGCAGCAGCA-CGCA

Variant names:

• chr12-8932728-CGCAGCA-C
• rs368945524
• NM_004426.3:c.1284_1289delGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM4 BP6_Moderate BS2

The NM_004426.3(PHC1):​c.1284_1289delGCAGCA​(p.Gln429_Gln430del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 151,848 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (4 hom., cov: 27)
  • Exomes 𝑓: 0.0020 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: PHC1 NM_004426.3 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.09
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_004426.3.
• BP6: Variant 12-8932728-CGCAGCA-C is Benign according to our data. Variant chr12-8932728-CGCAGCA-C is described in ClinVar as Benign. ClinVar VariationId is 376844.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC1	NM_004426.3	c.1284_1289delGCAGCA	p.Gln429_Gln430del	disruptive_inframe_deletion	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.1284_1289delGCAGCA	p.Gln429_Gln430del	disruptive_inframe_deletion	Exon 8 of 15	1	NM_004426.3	ENSP00000437659.1

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2812 AN: 151732 Hom.: 4 Cov.: 27

Gnomad AFR AF: 0.0622

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00385 AC: 955 AN: 248330 AF XY: 0.00285

Gnomad AFR exome AF: 0.0498

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.00164

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00197 AC: 2880 AN: 1460808 Hom.: 1 AF XY: 0.00170 AC XY: 1236 AN XY: 726696

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

African (AFR) AF: 0.0619 AC: 2061 AN: 33302

American (AMR) AF: 0.00671 AC: 300 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5758

European-Non Finnish (NFE) AF: 0.000224 AC: 249 AN: 1111252

Other (OTH) AF: 0.00396 AC: 239 AN: 60336

⚠️ 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 AF: 0.0185 AC: 2815 AN: 151848 Hom.: 4 Cov.: 27 AF XY: 0.0178 AC XY: 1324 AN XY: 74230

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

African (AFR) AF: 0.0621 AC: 2556 AN: 41172

American (AMR) AF: 0.0141 AC: 215 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67994

Other (OTH) AF: 0.0118 AC: 25 AN: 2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000840 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.1
Mutation Taster		=82/118	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs368945524; hg19: chr12-9085324;