3-170106944-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024947.4(PHC3):c.2356A>G(p.Thr786Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000253 in 1,581,540 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

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

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PHC3
NM_024947.4 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.06

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04355514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC3	NM_024947.4 link	c.2356A>G	p.Thr786Ala	missense_variant, splice_region_variant	Exon 12 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.2356A>G	p.Thr786Ala	missense_variant, splice_region_variant	Exon 12 of 15	1	NM_024947.4	ENSP00000420294.1	Q8NDX5-7
PHC3	ENST00000494943.5 link	c.2320A>G	p.Thr774Ala	missense_variant, splice_region_variant	Exon 12 of 15	1		ENSP00000420271.1	Q8NDX5-1
PHC3	ENST00000467570.5 link	c.2197A>G	p.Thr733Ala	missense_variant, splice_region_variant	Exon 11 of 13	2		ENSP00000419089.1	E7EX82

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

AF:

0.00000210

AC:

AN:

1429384

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

711294

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31534

American (AMR)

AF:

0.00

AC:

AN:

36076

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24768

East Asian (EAS)

AF:

0.00

AC:

AN:

39200

South Asian (SAS)

AF:

0.00

AC:

AN:

80694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52900

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5614

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1099662

Other (OTH)

AF:

0.00

AC:

AN:

58936

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2356A>G (p.T786A) alteration is located in exon 12 (coding exon 12) of the PHC3 gene. This alteration results from a A to G substitution at nucleotide position 2356, causing the threonine (T) at amino acid position 786 to be replaced by an alanine (A). 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

0.067

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.057

.;T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.76

T;T;T

M_CAP

Benign

0.0056

MetaRNN

Benign

0.044

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

.;N;.

PhyloP100

1.1

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.11

N;N;N

REVEL

Benign

0.017

Sift

Benign

0.20

T;T;T

Sift4G

Benign

0.83

T;T;T

Polyphen

0.0040

B;B;B

Vest4

0.11

MutPred

0.25

.;Gain of glycosylation at T774 (P = 0.0035);.;

MVP

0.12

MPC

0.13

ClinPred

0.18

GERP RS

3.7

Varity_R

0.029

gMVP

0.19

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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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3-170106944-T-C

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