chr12-8933055-G-A

Variant names:

• chr12-8933055-G-A
• rs878853029
• NM_004426.3:c.1598G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4 BP6_Moderate

The NM_004426.3(PHC1):​c.1598G>A​(p.Arg533Gln) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000078 (0 hom., cov: 19)
  • Exomes 𝑓: 0.000018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PHC1 NM_004426.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 8.37
• 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2760085).
• BP6: Variant 12-8933055-G-A is Benign according to our data. Variant chr12-8933055-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 235403.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHC1	NM_004426.3	MANE Select	c.1598G>A	p.Arg533Gln	missense	Exon 8 of 15	NP_004417.2	P78364
	PHC1	NM_001413738.1		c.1598G>A	p.Arg533Gln	missense	Exon 8 of 15	NP_001400667.1	P78364
	PHC1	NM_001413739.1		c.1592G>A	p.Arg531Gln	missense	Exon 8 of 15	NP_001400668.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHC1	ENST00000544916.6	TSL:1 MANE Select	c.1598G>A	p.Arg533Gln	missense	Exon 8 of 15	ENSP00000437659.1	P78364
	PHC1	ENST00000543824.5	TSL:1	c.1598G>A	p.Arg533Gln	missense	Exon 9 of 16	ENSP00000440674.1	P78364
	PHC1	ENST00000433083.6	TSL:1	c.1463G>A	p.Arg488Gln	missense	Exon 7 of 14	ENSP00000399194.2	J3KQH6

Frequencies

GnomAD3 genomes AF: 0.00000775 AC: 1 AN: 128988 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000163

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000178 AC: 10 AN: 560286 Hom.: 0 Cov.: 7 AF XY: 0.0000206 AC XY: 6 AN XY: 290620

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

African (AFR) AF: 0.00 AC: 0 AN: 15368

American (AMR) AF: 0.0000384 AC: 1 AN: 26068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15400

East Asian (EAS) AF: 0.00 AC: 0 AN: 31670

South Asian (SAS) AF: 0.00 AC: 0 AN: 50466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2224

European-Non Finnish (NFE) AF: 0.0000224 AC: 8 AN: 356868

Other (OTH) AF: 0.0000337 AC: 1 AN: 29646

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000372277), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000775 AC: 1 AN: 128988 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 60846

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

African (AFR) AF: 0.00 AC: 0 AN: 33724

American (AMR) AF: 0.00 AC: 0 AN: 11856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3208

East Asian (EAS) AF: 0.00 AC: 0 AN: 4788

South Asian (SAS) AF: 0.00 AC: 0 AN: 3554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7766

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

European-Non Finnish (NFE) AF: 0.0000163 AC: 1 AN: 61342

Other (OTH) AF: 0.00 AC: 0 AN: 1624

⚠️ 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: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely 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
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		8.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.26
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.37
MutPred		0.36		Loss of solvent accessibility (P = 1e-04)
MVP		0.64
MPC		0.86
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.19
gMVP		0.38
Mutation Taster		=77/23	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: rs878853029; hg19: chr12-9085651;