12-8921619-T-G

Variant names:

• chr12-8921619-T-G
• rs1419370980
• NM_004426.3:c.325T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004426.3(PHC1):​c.325T>G​(p.Ser109Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S109P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PHC1 NM_004426.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.08
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14719191).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC1	NM_004426.3	c.325T>G	p.Ser109Ala	missense_variant	Exon 5 of 15	ENST00000544916.6	NP_004417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHC1	ENST00000544916.6	c.325T>G	p.Ser109Ala	missense_variant	Exon 5 of 15	1	NM_004426.3	ENSP00000437659.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461384 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727014

African (AFR) AF: 0.0000299 AC: 1 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111860

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0079	T;T;T;T;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.59	T;.;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;L;.;L;.;.
PhyloP100		4.1
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.22	N;N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.54	T;T;T;T;T;T
Sift4G	Benign	0.64	T;T;T;T;T;T
Polyphen		0.94	.;P;.;P;.;.
Vest4		0.42, 0.42, 0.43
MutPred		0.22		Gain of catalytic residue at T108 (P = 0.0244);Gain of catalytic residue at T108 (P = 0.0244);.;Gain of catalytic residue at T108 (P = 0.0244);Gain of catalytic residue at T108 (P = 0.0244);.;
MVP		0.45
MPC		1.4
ClinPred		0.76	D
GERP RS		4.5
Varity_R		0.095
gMVP		0.54
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1419370980; hg19: chr12-9074215;