rs144307674

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.144

Publications

4 publications found

Variant links:

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

PHC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC1	NM_004426.3 link	c.2110G>A	p.Ala704Thr	missense_variant	Exon 10 of 15	ENST00000544916.6	NP_004417.2	P78364Q6GMQ3Q6N083

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHC1	ENST00000544916.6 link	c.2110G>A	p.Ala704Thr	missense_variant	Exon 10 of 15	1	NM_004426.3	ENSP00000437659.1		P78364

Frequencies

GnomAD3 genomes

AF:

0.00239

AC:

364

AN:

152060

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.00299

AC XY:

2175

AN XY:

727186

show subpopulations

African (AFR)

AF:

0.000597

AC:

AN:

33478

American (AMR)

AF:

0.00490

AC:

219

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000707

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.000711

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00348

AC:

3868

AN:

1111876

Other (OTH)

AF:

0.00376

AC:

227

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

213

427

640

854

1067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

162

324

486

648

810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00239

AC:

364

AN:

152178

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41528

American (AMR)

AF:

0.00661

AC:

101

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000624

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.000850

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00319

AC:

217

AN:

68010

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00175

Hom.:

Bravo

AF:

0.00291

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00337

AC:

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

LINK: link

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.065

T;T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.73

.;T;T

MetaRNN

Benign

0.0022

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.26

N;.;N

PhyloP100

-0.14

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.16

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.94

T;T;T

Sift4G

Benign

0.92

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.028

MVP

0.16

MPC

0.73

ClinPred

0.00037

GERP RS

2.4

Varity_R

0.027

gMVP

0.18

Mutation Taster

=91/9

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over