22-44883229-G-C

Variant names:

• chr22-44883229-G-C
• rs2070769083
• NM_138415.5:c.1453C>G

Variant summary

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

The NM_138415.5(PHF21B):​c.1453C>G​(p.Leu485Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,644 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: 0.0000021 (0 hom.)
• Consequence: PHF21B NM_138415.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.41

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.1453C>G	p.Leu485Val	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.1453C>G	p.Leu485Val	missense_variant	Exon 13 of 13	1	NM_138415.5	ENSP00000324403.5
PHF21B	ENST00000629843.3	c.1327C>G	p.Leu443Val	missense_variant	Exon 13 of 13	1		ENSP00000487086.1
PHF21B	ENST00000396103.7	c.1291C>G	p.Leu431Val	missense_variant	Exon 13 of 13	2
PHF21B	ENST00000403565.5	c.841C>G	p.Leu281Val	missense_variant	Exon 14 of 14	2		ENSP00000385053.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461644 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1453C>G (p.L485V) alteration is located in exon 13 (coding exon 13) of the PHF21B gene. This alteration results from a C to G substitution at nucleotide position 1453, causing the leucine (L) at amino acid position 485 to be replaced by a valine (V). 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	0.20
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	.;.;T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	1.9	.;.;L;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N;.;N;.
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D;.;D;.
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.59
MutPred		0.32		.;.;Gain of MoRF binding (P = 0.0759);.;
MVP		0.49
MPC		0.95
ClinPred		0.89	D
GERP RS		3.5
Varity_R		0.44
gMVP		0.53

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

Other links and lift over

dbSNP: rs2070769083; hg19: chr22-45279109;