22-44883104-G-T

Variant names:

• chr22-44883104-G-T
• NM_138415.5:c.1578C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138415.5(PHF21B):​c.1578C>A​(p.His526Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PHF21B NM_138415.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.20

Genes affected

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

ACMG classification

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=0.029924244).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF21B	NM_138415.5	c.1578C>A	p.His526Gln	missense_variant	Exon 13 of 13	ENST00000313237.10	NP_612424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF21B	ENST00000313237.10	c.1578C>A	p.His526Gln	missense_variant	Exon 13 of 13	1	NM_138415.5	ENSP00000324403.5
PHF21B	ENST00000629843.3	c.1452C>A	p.His484Gln	missense_variant	Exon 13 of 13	1		ENSP00000487086.1
PHF21B	ENST00000396103.7	c.1416C>A	p.His472Gln	missense_variant	Exon 13 of 13	2
PHF21B	ENST00000403565.5	c.966C>A	p.His322Gln	missense_variant	Exon 14 of 14	2		ENSP00000385053.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459232 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 725952

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1578C>A (p.H526Q) alteration is located in exon 13 (coding exon 13) of the PHF21B gene. This alteration results from a C to A substitution at nucleotide position 1578, causing the histidine (H) at amino acid position 526 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	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.2
DANN	Benign	0.95
DEOGEN2	Benign	0.0019	.;.;T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.58	T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.030	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.2	.;.;L;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.62	N;.;N;.
REVEL	Benign	0.20
Sift	Benign	0.14	T;.;T;.
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.033
MutPred		0.087		.;.;Gain of phosphorylation at T523 (P = 0.2486);.;
MVP		0.082
MPC		0.28
ClinPred		0.079	T
GERP RS		-0.31
Varity_R		0.066
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-45278984;