rs140650800

Variant names:

• chr12-8919803-C-T
• rs140650800
• NM_004426.3:c.162C>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.162C>T​(p.His54His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00075 in 1,612,592 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (1 hom.)
• Consequence: PHC1 NM_004426.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.64
• 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=-0.33).
• BP6: Variant 12-8919803-C-T is Benign according to our data. Variant chr12-8919803-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 436300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.64 with no splicing effect.

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.162C>T	p.His54His	synonymous	Exon 3 of 15	NP_004417.2
	PHC1	NM_001413738.1		c.162C>T	p.His54His	synonymous	Exon 3 of 15	NP_001400667.1
	PHC1	NM_001413739.1		c.162C>T	p.His54His	synonymous	Exon 3 of 15	NP_001400668.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHC1	ENST00000544916.6	TSL:1 MANE Select	c.162C>T	p.His54His	synonymous	Exon 3 of 15	ENSP00000437659.1
	PHC1	ENST00000543824.5	TSL:1	c.162C>T	p.His54His	synonymous	Exon 4 of 16	ENSP00000440674.1
	PHC1	ENST00000540574.5	TSL:1	n.162C>T		non_coding_transcript_exon	Exon 3 of 18	ENSP00000444308.1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000602 AC: 150 AN: 249286 AF XY: 0.000638

Gnomad AFR exome AF: 0.0000635

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.000601

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00104

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000773 AC: 1129 AN: 1460258 Hom.: 1 Cov.: 31 AF XY: 0.000775 AC XY: 563 AN XY: 726316

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.000292 AC: 13 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.000345 AC: 9 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000361 AC: 31 AN: 85898

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53356

Middle Eastern (MID) AF: 0.000185 AC: 1 AN: 5394

European-Non Finnish (NFE) AF: 0.000919 AC: 1021 AN: 1111520

Other (OTH) AF: 0.000779 AC: 47 AN: 60326

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74488

African (AFR) AF: 0.000241 AC: 10 AN: 41566

American (AMR) AF: 0.000850 AC: 13 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000960 Hom.: 0

Bravo AF: 0.000582

EpiCase AF: 0.000818

EpiControl AF: 0.000830

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.71
PhyloP100		2.6
Mutation Taster		=282/18	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: rs140650800; hg19: chr12-9072399;