20-35863337-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_016436.5(PHF20):c.745C>T(p.Pro249Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PHF20 NM_016436.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

Genes affected

PHF20 (HGNC:16098): (PHD finger protein 20) Predicted to enable DNA binding activity and metal ion binding activity. Involved in histone H4-K16 acetylation; histone H4-K5 acetylation; and histone H4-K8 acetylation. Located in cytosol; nuclear membrane; and nucleoplasm. Part of MLL1 complex and histone acetyltransferase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PHF20
• BP4: Computational evidence support a benign effect (MetaRNN=0.11762902).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF20	NM_016436.5	c.745C>T	p.Pro249Ser	missense_variant	6/18	ENST00000374012.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF20	ENST00000374012.8	c.745C>T	p.Pro249Ser	missense_variant	6/18	1	NM_016436.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460006 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726360

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: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2024

The c.745C>T (p.P249S) alteration is located in exon 6 (coding exon 5) of the PHF20 gene. This alteration results from a C to T substitution at nucleotide position 745, causing the proline (P) at amino acid position 249 to be replaced by a serine (S). 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	0.084
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.018	T;T;T;.
Eigen	Benign	-0.063
Eigen_PC	Benign	0.011
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;.;.
MutationTaster	Benign	0.77	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.76	N;N;N;N
REVEL	Benign	0.076
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Benign	0.70	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.043
MutPred		0.12		Gain of phosphorylation at P249 (P = 0.014);Gain of phosphorylation at P249 (P = 0.014);Gain of phosphorylation at P249 (P = 0.014);.;
MVP		0.39
MPC		0.52
ClinPred		0.39	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.41

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: chr20-34451259; COSMIC: COSV100179941; COSMIC: COSV100179941;