rs144307674

Variant names:

• chr12-8934335-G-A
• rs144307674
• NM_004426.3:c.2110G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004426.3(PHC1):​c.2110G>A​(p.Ala704Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00298 in 1,613,916 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A704S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (9 hom.)
• Consequence: PHC1 NM_004426.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.144
• Publications: 4 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021620095).
• BP6: Variant 12-8934335-G-A is Benign according to our data. Variant chr12-8934335-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 436302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.2110G>A	p.Ala704Thr	missense	Exon 10 of 15	NP_004417.2
	PHC1	NM_001413738.1		c.2110G>A	p.Ala704Thr	missense	Exon 10 of 15	NP_001400667.1
	PHC1	NM_001413739.1		c.2104G>A	p.Ala702Thr	missense	Exon 10 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.2110G>A	p.Ala704Thr	missense	Exon 10 of 15	ENSP00000437659.1
	PHC1	ENST00000543824.5	TSL:1	c.2110G>A	p.Ala704Thr	missense	Exon 11 of 16	ENSP00000440674.1
	PHC1	ENST00000433083.6	TSL:1	c.1975G>A	p.Ala659Thr	missense	Exon 9 of 14	ENSP00000399194.2

Frequencies

GnomAD3 genomes AF: 0.00239 AC: 364 AN: 152060 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000624

Gnomad FIN AF: 0.000850

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00242 AC: 609 AN: 251412 AF XY: 0.00241

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00315

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00304 AC: 4443 AN: 1461738 Hom.: 9 Cov.: 33 AF XY: 0.00299 AC XY: 2175 AN XY: 727186

African (AFR) AF: 0.000597 AC: 20 AN: 33478

American (AMR) AF: 0.00490 AC: 219 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000707 AC: 61 AN: 86252

European-Finnish (FIN) AF: 0.000711 AC: 38 AN: 53420

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.00348 AC: 3868 AN: 1111876

Other (OTH) AF: 0.00376 AC: 227 AN: 60392

GnomAD4 genome AF: 0.00239 AC: 364 AN: 152178 Hom.: 3 Cov.: 32 AF XY: 0.00208 AC XY: 155 AN XY: 74402

African (AFR) AF: 0.000626 AC: 26 AN: 41528

American (AMR) AF: 0.00661 AC: 101 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4806

European-Finnish (FIN) AF: 0.000850 AC: 9 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00319 AC: 217 AN: 68010

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00291

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00237 AC: 288

EpiCase AF: 0.00316

EpiControl AF: 0.00385

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PHC1: BP4, BS2

not specified Benign:1

Aug 12, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PHC1-related disorder Benign:1

Sep 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	15
DANN	Benign	0.57
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.26	N
PhyloP100		-0.14
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.14
Sift	Benign	0.94	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.028
MVP		0.16
MPC		0.73
ClinPred		0.00037	T
GERP RS		2.4
Varity_R		0.027
gMVP		0.18
Mutation Taster		=91/9	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: rs144307674; hg19: chr12-9086931; COSMIC: COSV99067617; COSMIC: COSV99067617;