rs1805733

Variant names:

• chr12-8936676-A-C
• rs1805733
• NM_004426.3:c.2369-180A>C

Your query was ambiguous. Multiple possible variants found:

• chr12-8936676-A-C
• chr12-8936676-A-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.2369-180A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 151,964 control chromosomes in the GnomAD database, including 11,465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.37 (11465 hom., cov: 31)
• Consequence: PHC1 NM_004426.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.77
• Publications: 8 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=-0.78).
• BP6: Variant 12-8936676-A-C is Benign according to our data. Variant chr12-8936676-A-C is described in ClinVar as Benign. ClinVar VariationId is 1227373.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.446 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004426.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHC1	NM_004426.3	MANE Select	c.2369-180A>C		intron	N/A	NP_004417.2
	PHC1	NM_001413738.1		c.2369-180A>C		intron	N/A	NP_001400667.1
	PHC1	NM_001413739.1		c.2363-180A>C		intron	N/A	NP_001400668.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHC1	ENST00000544916.6	TSL:1 MANE Select	c.2369-180A>C		intron	N/A	ENSP00000437659.1
	PHC1	ENST00000543824.5	TSL:1	c.2369-180A>C		intron	N/A	ENSP00000440674.1
	PHC1	ENST00000433083.6	TSL:1	c.2234-180A>C		intron	N/A	ENSP00000399194.2

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56309 AN: 151846 Hom.: 11459 Cov.: 31

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.313

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.469

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.463

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.459

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.382

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

GnomAD4 genome AF: 0.371 AC: 56325 AN: 151964 Hom.: 11465 Cov.: 31 AF XY: 0.374 AC XY: 27733 AN XY: 74250

African (AFR) AF: 0.191 AC: 7941 AN: 41468

American (AMR) AF: 0.385 AC: 5881 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.469 AC: 1627 AN: 3470

East Asian (EAS) AF: 0.413 AC: 2132 AN: 5158

South Asian (SAS) AF: 0.462 AC: 2220 AN: 4810

European-Finnish (FIN) AF: 0.475 AC: 5005 AN: 10526

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30283 AN: 67958

Other (OTH) AF: 0.386 AC: 814 AN: 2110

Alfa AF: 0.407 Hom.: 8234

Bravo AF: 0.357

Asia WGS AF: 0.420 AC: 1463 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.4
DANN	Benign	0.56
PhyloP100		1.8
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: rs1805733; hg19: chr12-9089272;