22-44889763-C-G

Variant names:

• chr22-44889763-C-G
• rs2070927733
• NM_138415.5:c.1035G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138415.5(PHF21B):​c.1035G>C​(p.Trp345Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: PHF21B NM_138415.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.69

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF21B	NM_138415.5	c.1035G>C	p.Trp345Cys	missense_variant	Exon 9 of 13	ENST00000313237.10	NP_612424.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF21B	ENST00000313237.10	c.1035G>C	p.Trp345Cys	missense_variant	Exon 9 of 13	1	NM_138415.5	ENSP00000324403.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 33

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1035G>C (p.W345C) alteration is located in exon 9 (coding exon 9) of the PHF21B gene. This alteration results from a G to C substitution at nucleotide position 1035, causing the tryptophan (W) at amino acid position 345 to be replaced by a cysteine (C). 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	Pathogenic	0.76
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	.;.;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.9	.;.;L;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.9	D;.;D;.
REVEL	Benign	0.26
Sift	Benign	0.075	T;.;D;.
Sift4G	Benign	0.19	T;T;T;T
Polyphen		1.0	D;.;D;D
Vest4		0.62
MutPred		0.53		.;.;Loss of catalytic residue at W345 (P = 0.001);.;
MVP		0.043
MPC		1.1
ClinPred		0.98	D
GERP RS		4.5
Varity_R		0.40
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs2070927733; hg19: chr22-45285643;