Genetic Variant PHF21B:p.Ala373Thr (chr22-44888043-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138415.5(PHF21B):c.1117G>A(p.Ala373Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000057 in 1,403,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

PHF21B
NM_138415.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.63

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138415.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHF21B	NM_138415.5	MANE Select	c.1117G>A	p.Ala373Thr	missense	Exon 10 of 13	NP_612424.1	A0A0S2Z6R3
PHF21B	NM_001135862.3		c.991G>A	p.Ala331Thr	missense	Exon 11 of 14	NP_001129334.1	A0A0S2Z665
PHF21B	NM_001413063.1		c.991G>A	p.Ala331Thr	missense	Exon 10 of 13	NP_001399992.1	Q96EK2-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHF21B	ENST00000313237.10	TSL:1 MANE Select	c.1117G>A	p.Ala373Thr	missense	Exon 10 of 13	ENSP00000324403.5	Q96EK2-1
PHF21B	ENST00000629843.3	TSL:1	c.991G>A	p.Ala331Thr	missense	Exon 10 of 13	ENSP00000487086.1	Q96EK2-3
PHF21B	ENST00000420689.2	TSL:5	c.955G>A	p.Ala319Thr	missense	Exon 10 of 13	ENSP00000401294.2	Q96EK2-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000187

AC:

AN:

160782

AF XY:

0.0000351

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000319

Gnomad OTH exome

AF:

0.000228

GnomAD4 exome

AF:

0.00000570

AC:

AN:

1403862

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

693126

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32376

American (AMR)

AF:

0.00

AC:

AN:

36224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25104

East Asian (EAS)

AF:

0.00

AC:

AN:

36918

South Asian (SAS)

AF:

0.00

AC:

AN:

79530

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4480

European-Non Finnish (NFE)

AF:

0.00000739

AC:

AN:

1082550

Other (OTH)

AF:

0.00

AC:

AN:

58076

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000646934), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0097

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.0

PhyloP100

4.6

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.4

REVEL

Benign

0.27

Sift

Benign

0.082

Sift4G

Benign

0.070

Polyphen

1.0

Vest4

0.63

MutPred

0.43

Gain of phosphorylation at T369 (P = 0.1133)

MVP

0.17

MPC

0.36

ClinPred

0.60

GERP RS

4.0

Varity_R

0.25

gMVP

0.33

Mutation Taster

=59/41

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over