3-170113482-T-C

Variant names:

• chr3-170113482-T-C
• NM_024947.4:c.2231A>G

Variant summary

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

The NM_024947.4(PHC3):​c.2231A>G​(p.Lys744Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHC3 NM_024947.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.75
• Publications: 0 publications found

Genes affected

PHC3 (HGNC:15682): (polyhomeotic homolog 3) Predicted to enable chromatin binding activity and histone binding activity. Predicted to be involved in negative regulation of transcription, DNA-templated. Located in nucleoplasm. Part of PRC1 complex. [provided by Alliance of Genome Resources, Apr 2022]

LOC105374209 (HGNC:):

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=0.17089453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC3	NM_024947.4	c.2231A>G	p.Lys744Arg	missense_variant	Exon 11 of 15	ENST00000495893.7	NP_079223.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHC3	ENST00000495893.7	c.2231A>G	p.Lys744Arg	missense_variant	Exon 11 of 15	1	NM_024947.4	ENSP00000420294.1
PHC3	ENST00000494943.5	c.2195A>G	p.Lys732Arg	missense_variant	Exon 11 of 15	1		ENSP00000420271.1
PHC3	ENST00000467570.5	c.2072A>G	p.Lys691Arg	missense_variant	Exon 10 of 13	2		ENSP00000419089.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2231A>G (p.K744R) alteration is located in exon 11 (coding exon 11) of the PHC3 gene. This alteration results from a A to G substitution at nucleotide position 2231, causing the lysine (K) at amino acid position 744 to be replaced by an arginine (R). 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	0.086
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.81	.;L;.
PhyloP100		5.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.098
Sift	Benign	0.049	D;D;D
Sift4G	Benign	0.082	T;T;T
Polyphen		0.36	B;P;P
Vest4		0.26
MutPred		0.40		.;Loss of methylation at K732 (P = 0.0039);.;
MVP		0.41
MPC		0.24
ClinPred		0.78	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.30
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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

hg19: chr3-169831270;