chr3-170102857-C-T

Variant names:

• chr3-170102857-C-T
• rs190320073
• NM_024947.4:c.2546G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_024947.4(PHC3):​c.2546G>A​(p.Arg849His) variant causes a missense change. The variant allele was found at a frequency of 0.000359 in 1,613,846 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (2 hom.)
• Consequence: PHC3 NM_024947.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.36
• Publications: 3 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034894288).
• BS2: High AC in GnomAd4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHC3	NM_024947.4	c.2546G>A	p.Arg849His	missense_variant	Exon 13 of 15	ENST00000495893.7	NP_079223.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHC3	ENST00000495893.7	c.2546G>A	p.Arg849His	missense_variant	Exon 13 of 15	1	NM_024947.4	ENSP00000420294.1
PHC3	ENST00000494943.5	c.2510G>A	p.Arg837His	missense_variant	Exon 13 of 15	1		ENSP00000420271.1
PHC3	ENST00000467570.5	c.2387G>A	p.Arg796His	missense_variant	Exon 12 of 13	2		ENSP00000419089.1
PHC3	ENST00000484068.5	c.41G>A	p.Arg14His	missense_variant	Exon 1 of 4	4		ENSP00000418835.1

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000583 AC: 145 AN: 248614 AF XY: 0.000578

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000511

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000356 AC: 521 AN: 1461530 Hom.: 2 Cov.: 32 AF XY: 0.000348 AC XY: 253 AN XY: 727058

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.000693 AC: 37 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000407 AC: 452 AN: 1111784

Other (OTH) AF: 0.000414 AC: 25 AN: 60358

GnomAD4 genome AF: 0.000387 AC: 59 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74460

African (AFR) AF: 0.000120 AC: 5 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000566 AC: 6 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000661 AC: 45 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000515 Hom.: 0

Bravo AF: 0.000212

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.000487 AC: 4

ExAC AF: 0.000910 AC: 110

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2546G>A (p.R849H) alteration is located in exon 13 (coding exon 13) of the PHC3 gene. This alteration results from a G to A substitution at nucleotide position 2546, causing the arginine (R) at amino acid position 849 to be replaced by a histidine (H). 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	0.14
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	.;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.035	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.9	.;L;.
PhyloP100		4.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.093
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.87	P;P;D
Vest4		0.39
MVP		0.37
MPC		0.45
ClinPred		0.11	T
GERP RS		5.7
PromoterAI		0.051	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.52
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs190320073; hg19: chr3-169820645;