Genetic Variant PHF21B:p.Thr502Pro (chr22-44883178-T-G) – 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.1504A>C(p.Thr502Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,613,238 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

PHF21B
NM_138415.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.90

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=0.16470408).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF21B	NM_138415.5 link	c.1504A>C	p.Thr502Pro	missense_variant	Exon 13 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.1504A>C	p.Thr502Pro	missense_variant	Exon 13 of 13	1	NM_138415.5	ENSP00000324403.5	Q96EK2-1
PHF21B	ENST00000629843.3 link	c.1378A>C	p.Thr460Pro	missense_variant	Exon 13 of 13	1		ENSP00000487086.1	Q96EK2-3
PHF21B	ENST00000396103.7 link	c.1342A>C	p.Thr448Pro	missense_variant	Exon 13 of 13	2			Q96EK2-4
PHF21B	ENST00000403565.5 link	c.892A>C	p.Thr298Pro	missense_variant	Exon 14 of 14	2		ENSP00000385053.2	B1AHC5

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000360

AC:

AN:

249658

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135048

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000868

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:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1461170

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000105

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.000242

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000331

Hom.:

Bravo

AF:

0.000132

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1504A>C (p.T502P) alteration is located in exon 13 (coding exon 13) of the PHF21B gene. This alteration results from a A to C substitution at nucleotide position 1504, causing the threonine (T) at amino acid position 502 to be replaced by a proline (P). 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

0.085

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0040

.;.;T;.

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.75

T;T;T;T

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.16

T;T;T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.5

.;.;L;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.7

N;.;N;.

REVEL

Uncertain

0.46

Sift

Uncertain

0.0020

D;.;D;.

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

0.75

P;.;D;D

Vest4

0.29

MVP

0.20

MPC

0.72

ClinPred

0.14

GERP RS

0.12

Varity_R

0.35

gMVP

0.67

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