dbSNP rs763467497: PHC3:p.Arg895Cys (chr3-170102629-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_024947.4(PHC3):c.2683C>T(p.Arg895Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PHC3
NM_024947.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.99

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.4125532).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC3	NM_024947.4 link	c.2683C>T	p.Arg895Cys	missense_variant	Exon 14 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.2683C>T	p.Arg895Cys	missense_variant	Exon 14 of 15	1	NM_024947.4	ENSP00000420294.1	Q8NDX5-7
PHC3	ENST00000494943.5 link	c.2647C>T	p.Arg883Cys	missense_variant	Exon 14 of 15	1		ENSP00000420271.1	Q8NDX5-1
PHC3	ENST00000484068.5 link	c.178C>T	p.Arg60Cys	missense_variant	Exon 2 of 4	4		ENSP00000418835.1	H7C528
PHC3	ENST00000467570.5 link	c.*12C>T		3_prime_UTR_variant	Exon 13 of 13	2		ENSP00000419089.1	E7EX82

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248736

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461646

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727112

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111840

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2683C>T (p.R895C) alteration is located in exon 14 (coding exon 14) of the PHC3 gene. This alteration results from a C to T substitution at nucleotide position 2683, causing the arginine (R) at amino acid position 895 to be replaced by a cysteine (C). 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

Pathogenic

0.80

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.21

.;T

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.063

MetaRNN

Benign

0.41

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.0

.;M

PhyloP100

4.0

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.19

Sift

Uncertain

0.0020

D;D

Sift4G

Benign

0.12

T;T

Polyphen

1.0

D;D

Vest4

0.49

MutPred

0.36

.;Gain of glycosylation at S886 (P = 2e-04);

MVP

0.27

MPC

0.69

ClinPred

0.85

GERP RS

5.1

PromoterAI

-0.083

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.57

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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rs763467497

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over