Genetic Variant PHC3:p.Pro841Thr (chr3-170102882-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024947.4(PHC3):c.2521C>A(p.Pro841Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P841S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

PHC3
NM_024947.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.00

Publications

0 publications found

Variant links:

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]

PHC3 links:

LOC105374209 (HGNC:):

LOC105374209 links:

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ACMG classification

Classification was made for transcript

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=0.079667956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC3	NM_024947.4 link	c.2521C>A	p.Pro841Thr	missense_variant	Exon 13 of 15	ENST00000495893.7	NP_079223.3	Q8NDX5-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PHC3	ENST00000495893.7 link	c.2521C>A	p.Pro841Thr	missense_variant	Exon 13 of 15	1	NM_024947.4	ENSP00000420294.1	Q8NDX5-7
PHC3	ENST00000494943.5 link	c.2485C>A	p.Pro829Thr	missense_variant	Exon 13 of 15	1		ENSP00000420271.1	Q8NDX5-1
PHC3	ENST00000467570.5 link	c.2362C>A	p.Pro788Thr	missense_variant	Exon 12 of 13	2		ENSP00000419089.1	E7EX82
PHC3	ENST00000484068.5 link	c.16C>A	p.Pro6Thr	missense_variant	Exon 1 of 4	4		ENSP00000418835.1	H7C528

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.054

.;T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Benign

0.0063

MetaRNN

Benign

0.080

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.1

.;L;.

PhyloP100

3.0

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.49

N;N;N

REVEL

Benign

0.053

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.17

T;T;T

Polyphen

0.014

B;B;B

Vest4

0.25

MutPred

0.16

.;Loss of loop (P = 0.0512);.;

MVP

0.13

MPC

0.23

ClinPred

0.21

GERP RS

5.7

PromoterAI

-0.0027

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.033

gMVP

0.37

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over