12-8930740-A-G

Variant names:

• chr12-8930740-A-G
• rs1805777
• NM_004426.3:c.918A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004426.3(PHC1):​c.918A>G​(p.Arg306Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (54764 hom., cov: 20)
  • Exomes 𝑓: 0.93 (467421 hom.)
  • Failed GnomAD Quality Control
• Consequence: PHC1 NM_004426.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.08
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 12-8930740-A-G is Benign according to our data. Variant chr12-8930740-A-G is described in ClinVar as Benign. ClinVar VariationId is 211899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.08 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.94 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.918A>G	p.Arg306Arg	synonymous	Exon 7 of 15	NP_004417.2
	PHC1	NM_001413738.1		c.918A>G	p.Arg306Arg	synonymous	Exon 7 of 15	NP_001400667.1
	PHC1	NM_001413739.1		c.912A>G	p.Arg304Arg	synonymous	Exon 7 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.918A>G	p.Arg306Arg	synonymous	Exon 7 of 15	ENSP00000437659.1
	PHC1	ENST00000543824.5	TSL:1	c.918A>G	p.Arg306Arg	synonymous	Exon 8 of 16	ENSP00000440674.1
	PHC1	ENST00000433083.6	TSL:1	c.783A>G	p.Arg261Arg	synonymous	Exon 6 of 14	ENSP00000399194.2

Frequencies

GnomAD3 genomes AF: 0.855 AC: 124731 AN: 145816 Hom.: 54741 Cov.: 20

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.950

Gnomad AMR AF: 0.900

Gnomad ASJ AF: 0.942

Gnomad EAS AF: 0.782

Gnomad SAS AF: 0.964

Gnomad FIN AF: 0.968

Gnomad MID AF: 0.916

Gnomad NFE AF: 0.946

Gnomad OTH AF: 0.858

GnomAD2 exomes AF: 0.860 AC: 107968 AN: 125610 AF XY: 0.870

Gnomad AFR exome AF: 0.482

Gnomad AMR exome AF: 0.900

Gnomad ASJ exome AF: 0.864

Gnomad EAS exome AF: 0.717

Gnomad FIN exome AF: 0.945

Gnomad NFE exome AF: 0.901

Gnomad OTH exome AF: 0.893

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.933 AC: 972484 AN: 1042370 Hom.: 467421 Cov.: 16 AF XY: 0.934 AC XY: 484419 AN XY: 518604

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

African (AFR) AF: 0.585 AC: 13794 AN: 23582

American (AMR) AF: 0.896 AC: 24366 AN: 27196

Ashkenazi Jewish (ASJ) AF: 0.917 AC: 17694 AN: 19306

East Asian (EAS) AF: 0.767 AC: 26283 AN: 34256

South Asian (SAS) AF: 0.964 AC: 60175 AN: 62428

European-Finnish (FIN) AF: 0.958 AC: 44558 AN: 46494

Middle Eastern (MID) AF: 0.906 AC: 3367 AN: 3718

European-Non Finnish (NFE) AF: 0.950 AC: 741018 AN: 780126

Other (OTH) AF: 0.911 AC: 41229 AN: 45264

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.855 AC: 124800 AN: 145932 Hom.: 54764 Cov.: 20 AF XY: 0.855 AC XY: 60498 AN XY: 70748

African (AFR) AF: 0.644 AC: 25365 AN: 39360

American (AMR) AF: 0.900 AC: 12964 AN: 14398

Ashkenazi Jewish (ASJ) AF: 0.942 AC: 3207 AN: 3406

East Asian (EAS) AF: 0.783 AC: 3892 AN: 4970

South Asian (SAS) AF: 0.964 AC: 4118 AN: 4272

European-Finnish (FIN) AF: 0.968 AC: 9535 AN: 9848

Middle Eastern (MID) AF: 0.920 AC: 265 AN: 288

European-Non Finnish (NFE) AF: 0.946 AC: 62925 AN: 66538

Other (OTH) AF: 0.858 AC: 1682 AN: 1960

Alfa AF: 0.893 Hom.: 10459

Bravo AF: 0.841

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Microcephaly 11, primary, autosomal recessive (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	10
DANN	Benign	0.64
PhyloP100		3.1
PromoterAI		-0.011	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: rs1805777; hg19: chr12-9083336; COSMIC: COSV70418015; COSMIC: COSV70418015;