22-44888001-G-A

Variant names:

• chr22-44888001-G-A
• rs759215827
• NM_138415.5:c.1159C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_138415.5(PHF21B):​c.1159C>T​(p.Pro387Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P387A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PHF21B NM_138415.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.28
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF21B	NM_138415.5	MANE Select	c.1159C>T	p.Pro387Ser	missense	Exon 10 of 13	NP_612424.1	A0A0S2Z6R3
	PHF21B	NM_001135862.3		c.1033C>T	p.Pro345Ser	missense	Exon 11 of 14	NP_001129334.1	A0A0S2Z665
	PHF21B	NM_001413063.1		c.1033C>T	p.Pro345Ser	missense	Exon 10 of 13	NP_001399992.1	Q96EK2-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF21B	ENST00000313237.10	TSL:1 MANE Select	c.1159C>T	p.Pro387Ser	missense	Exon 10 of 13	ENSP00000324403.5	Q96EK2-1
	PHF21B	ENST00000629843.3	TSL:1	c.1033C>T	p.Pro345Ser	missense	Exon 10 of 13	ENSP00000487086.1	Q96EK2-3
	PHF21B	ENST00000420689.2	TSL:5	c.997C>T	p.Pro333Ser	missense	Exon 10 of 13	ENSP00000401294.2	Q96EK2-4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1418662 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 701828

African (AFR) AF: 0.00 AC: 0 AN: 32934

American (AMR) AF: 0.00 AC: 0 AN: 38368

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24888

East Asian (EAS) AF: 0.00 AC: 0 AN: 38168

South Asian (SAS) AF: 0.00 AC: 0 AN: 79878

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4634

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091192

Other (OTH) AF: 0.00 AC: 0 AN: 58758

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74372

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68050

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.78		Gain of MoRF binding (P = 0.0508)
MVP		0.81
MPC		0.92
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.86
gMVP		0.46
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs759215827; hg19: chr22-45283881;