12-8917982-T-C

Variant names:

• chr12-8917982-T-C
• rs4883199
• NM_004426.3:c.114+191T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004426.3(PHC1):​c.114+191T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.86 in 152,218 control chromosomes in the GnomAD database, including 57,586 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.86 (57586 hom., cov: 33)
• Consequence: PHC1 NM_004426.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.519
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-8917982-T-C is Benign according to our data. Variant chr12-8917982-T-C is described in ClinVar as [Benign]. Clinvar id is 1178147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC1	NM_004426.3	c.114+191T>C		intron_variant	Intron 2 of 14	ENST00000544916.6	NP_004417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHC1	ENST00000544916.6	c.114+191T>C		intron_variant	Intron 2 of 14	1	NM_004426.3	ENSP00000437659.1

Frequencies

GnomAD3 genomes AF: 0.860 AC: 130881 AN: 152100 Hom.: 57560 Cov.: 33

Gnomad AFR AF: 0.665

Gnomad AMI AF: 0.950

Gnomad AMR AF: 0.904

Gnomad ASJ AF: 0.940

Gnomad EAS AF: 0.784

Gnomad SAS AF: 0.970

Gnomad FIN AF: 0.969

Gnomad MID AF: 0.915

Gnomad NFE AF: 0.946

Gnomad OTH AF: 0.862

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.860 AC: 130954 AN: 152218 Hom.: 57586 Cov.: 33 AF XY: 0.861 AC XY: 64071 AN XY: 74422

African (AFR) AF: 0.664 AC: 27549 AN: 41478

American (AMR) AF: 0.904 AC: 13833 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.940 AC: 3262 AN: 3472

East Asian (EAS) AF: 0.785 AC: 4070 AN: 5184

South Asian (SAS) AF: 0.970 AC: 4682 AN: 4826

European-Finnish (FIN) AF: 0.969 AC: 10277 AN: 10608

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.946 AC: 64321 AN: 68028

Other (OTH) AF: 0.863 AC: 1824 AN: 2114

Alfa AF: 0.912 Hom.: 23964

Bravo AF: 0.845

Asia WGS AF: 0.879 AC: 3057 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2021

GeneDx

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	-0.92
CADD	Benign	1.1
DANN	Benign	0.47
PhyloP100		-0.52
PromoterAI		0.043	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs4883199; hg19: chr12-9070578;