Genetic Variant PHF21B:p.Pro242Leu (chr22-44913928-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_138415.5(PHF21B):c.725C>T(p.Pro242Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000221 in 1,613,854 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00022 ( 1 hom. )

Consequence

PHF21B
NM_138415.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.74

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.014388114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF21B	NM_138415.5 link	c.725C>T	p.Pro242Leu	missense_variant	Exon 5 of 13	ENST00000313237.10	NP_612424.1	Q96EK2-1A0A0S2Z6R3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF21B	ENST00000313237.10 link	c.725C>T	p.Pro242Leu	missense_variant	Exon 5 of 13	1	NM_138415.5	ENSP00000324403.5		Q96EK2-1

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

151936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

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:

0.000280

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000394

AC:

AN:

251210

Hom.:

AF XY:

0.000354

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00162

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:

0.000335

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.000221

AC:

323

AN:

1461800

Hom.:

Cov.:

AF XY:

0.000209

AC XY:

152

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00163

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000203

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000224

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000280

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000209

Hom.:

Bravo

AF:

0.000332

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.725C>T (p.P242L) alteration is located in exon 5 (coding exon 5) of the PHF21B gene. This alteration results from a C to T substitution at nucleotide position 725, causing the proline (P) at amino acid position 242 to be replaced by a leucine (L). 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

0.10

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0066

.;.;T;.;.;.

Eigen

Benign

0.15

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

D;D;D;D;D;D

M_CAP

Benign

0.030

MetaRNN

Benign

0.014

T;T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

.;.;L;.;.;.

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-2.8

D;.;N;.;D;D

REVEL

Benign

0.069

Sift

Uncertain

0.0020

D;.;D;.;D;D

Sift4G

Benign

0.077

T;D;T;D;.;.

Polyphen

0.38

B;.;P;P;.;.

Vest4

0.22

MVP

0.12

MPC

0.80

ClinPred

0.14

GERP RS

3.6

Varity_R

0.079

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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