rs144307674

chr12-8934335-G-A

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• 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:3
• Conservation: PhyloP100: -0.144

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 436302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHC1	NM_004426.3	c.2110G>A	p.Ala704Thr	missense_variant	10/15	ENST00000544916.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHC1	ENST00000544916.6	c.2110G>A	p.Ala704Thr	missense_variant	10/15	1	NM_004426.3	P1

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

GnomAD3 exomes AF: 0.00242 AC: 609 AN: 251412 Hom.: 1 AF XY: 0.00241 AC XY: 327 AN XY: 135878

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 SAS exome AF: 0.000784

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

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00490

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000707

Gnomad4 FIN exome AF: 0.000711

Gnomad4 NFE exome AF: 0.00348

Gnomad4 OTH exome AF: 0.00376

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

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00661

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.000850

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00226 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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 12, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

PHC1: BP4, BS2 -

PHC1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2019

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	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	15
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	N
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.26	N;.;N
MutationTaster	Benign	0.94	N;N;N;N
PrimateAI	Benign	0.29	T
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	T
GERP RS		2.4
Varity_R		0.027
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs144307674; hg19: chr12-9086931; COSMIC: COSV99067617; COSMIC: COSV99067617;