rs749992978

Variant names:

• chr12-8917735-G-A
• rs749992978
• NM_004426.3:c.58G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004426.3(PHC1):​c.58G>A​(p.Gly20Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PHC1 NM_004426.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.20
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06243071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC1	NM_004426.3	c.58G>A	p.Gly20Ser	missense_variant	Exon 2 of 15	ENST00000544916.6	NP_004417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHC1	ENST00000544916.6	c.58G>A	p.Gly20Ser	missense_variant	Exon 2 of 15	1	NM_004426.3	ENSP00000437659.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000922 AC: 2 AN: 216976 AF XY: 0.0000169

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000146

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.01e-7 AC: 1 AN: 1426016 Hom.: 0 Cov.: 27 AF XY: 0.00000141 AC XY: 1 AN XY: 709104

⚠️ 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: 30568

American (AMR) AF: 0.00 AC: 0 AN: 38890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25294

East Asian (EAS) AF: 0.0000282 AC: 1 AN: 35522

South Asian (SAS) AF: 0.00 AC: 0 AN: 80822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53108

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097166

Other (OTH) AF: 0.00 AC: 0 AN: 58954

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.58G>A (p.G20S) alteration is located in exon 2 (coding exon 1) of the PHC1 gene. This alteration results from a G to A substitution at nucleotide position 58, causing the glycine (G) at amino acid position 20 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0063	T;T;T;T;T;.;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;.;T;T;D;D;D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.062	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.38	.;N;.;N;.;.;.
PhyloP100		3.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.37	N;N;N;N;N;N;N
REVEL	Benign	0.040
Sift	Benign	0.35	T;T;D;T;T;D;T
Sift4G	Benign	0.71	T;T;T;T;T;T;T
Polyphen		0.0010	.;B;.;B;.;.;.
Vest4		0.22, 0.26, 0.22
MutPred		0.18		Gain of phosphorylation at G20 (P = 0.0022);Gain of phosphorylation at G20 (P = 0.0022);Gain of phosphorylation at G20 (P = 0.0022);Gain of phosphorylation at G20 (P = 0.0022);Gain of phosphorylation at G20 (P = 0.0022);Gain of phosphorylation at G20 (P = 0.0022);Gain of phosphorylation at G20 (P = 0.0022);
MVP		0.40
MPC		0.75
ClinPred		0.22	T
GERP RS		4.0
PromoterAI		0.017	Neutral
Varity_R		0.068
gMVP		0.40
Mutation Taster		=270/30	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: rs749992978; hg19: chr12-9070331;