12-8919566-C-T

Variant names:

• chr12-8919566-C-T
• rs11611936
• NM_004426.3:c.115-190C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004426.3(PHC1):​c.115-190C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,058 control chromosomes in the GnomAD database, including 5,190 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.26 (5190 hom., cov: 32)
• Consequence: PHC1 NM_004426.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0790
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-8919566-C-T is Benign according to our data. Variant chr12-8919566-C-T is described in ClinVar as [Benign]. Clinvar id is 1272832.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.35 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC1	NM_004426.3	c.115-190C>T		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.115-190C>T		intron_variant	Intron 2 of 14	1	NM_004426.3	ENSP00000437659.1

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38939 AN: 151940 Hom.: 5188 Cov.: 32

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.314

Gnomad SAS AF: 0.364

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.264

Gnomad OTH AF: 0.272

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

GnomAD4 genome AF: 0.256 AC: 38946 AN: 152058 Hom.: 5190 Cov.: 32 AF XY: 0.254 AC XY: 18852 AN XY: 74338

African (AFR) AF: 0.239 AC: 9927 AN: 41452

American (AMR) AF: 0.223 AC: 3406 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1183 AN: 3470

East Asian (EAS) AF: 0.315 AC: 1627 AN: 5160

South Asian (SAS) AF: 0.364 AC: 1754 AN: 4818

European-Finnish (FIN) AF: 0.204 AC: 2156 AN: 10570

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.264 AC: 17931 AN: 67986

Other (OTH) AF: 0.269 AC: 567 AN: 2110

Alfa AF: 0.260 Hom.: 1822

Bravo AF: 0.254

Asia WGS AF: 0.320 AC: 1108 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	2.7
DANN	Benign	0.53
PhyloP100		0.079
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: rs11611936; hg19: chr12-9072162;