Genetic Variant PHF21B:p.Arg452Gln (chr22-44885448-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138415.5(PHF21B):c.1355G>A(p.Arg452Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,588,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

PHF21B
NM_138415.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.95

Variant links:

Genes affected

PHF21B (HGNC:25161): (PHD finger protein 21B) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

PHF21B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10662976).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF21B	NM_138415.5 link	c.1355G>A	p.Arg452Gln	missense_variant	Exon 12 of 13	ENST00000313237.10	NP_612424.1	Q96EK2-1A0A0S2Z6R3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PHF21B	ENST00000313237.10 link	c.1355G>A	p.Arg452Gln	missense_variant	Exon 12 of 13	1	NM_138415.5	ENSP00000324403.5	Q96EK2-1
PHF21B	ENST00000629843.3 link	c.1229G>A	p.Arg410Gln	missense_variant	Exon 12 of 13	1		ENSP00000487086.1	Q96EK2-3
PHF21B	ENST00000396103.7 link	c.1193G>A	p.Arg398Gln	missense_variant	Exon 12 of 13	2			Q96EK2-4
PHF21B	ENST00000403565.5 link	c.743G>A	p.Arg248Gln	missense_variant	Exon 13 of 14	2		ENSP00000385053.2	B1AHC5

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000191

AC:

AN:

209842

Hom.:

AF XY:

0.0000264

AC XY:

AN XY:

113454

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000434

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1436136

Hom.:

Cov.:

AF XY:

0.0000379

AC XY:

AN XY:

712242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000121

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000509

Gnomad4 OTH exome

AF:

0.0000337

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000582

Hom.:

Bravo

AF:

0.0000264

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

Jan 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1355G>A (p.R452Q) alteration is located in exon 12 (coding exon 12) of the PHF21B gene. This alteration results from a G to A substitution at nucleotide position 1355, causing the arginine (R) at amino acid position 452 to be replaced by a glutamine (Q). 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

0.068

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0033

.;.;T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.017

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.92

D;D;D;D

M_CAP

Benign

0.049

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.90

.;.;L;.

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.2

N;.;N;.

REVEL

Benign

0.051

Sift

Benign

0.071

T;.;D;.

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.15

B;.;P;B

Vest4

0.24

MutPred

0.18

.;.;Loss of MoRF binding (P = 0.0346);.;

MVP

0.14

MPC

0.62

ClinPred

0.30

GERP RS

4.3

Varity_R

0.17

gMVP

0.16

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over