X-53940270-C-T

Variant summary

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

The NM_015107.3(PHF8):c.2896G>A(p.Ala966Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,529 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: PHF8 NM_015107.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

Genes affected

PHF8 (HGNC:20672): (PHD finger protein 8) The protein encoded by this gene is a histone lysine demethylase that preferentially acts on histones in the monomethyl or dimethyl states. The encoded protein requires Fe(2+) ion, 2-oxoglutarate, and oxygen for its catalytic activity. The protein has an N-terminal PHD finger and a central Jumonji C domain. This gene is thought to function as a transcription activator. Defects in this gene are a cause of syndromic X-linked Siderius type intellectual disability (MRXSSD) and over-expression of this gene is associated with several forms of cancer. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

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, PHF8
• BP4: Computational evidence support a benign effect (MetaRNN=0.1132983).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF8	NM_015107.3	c.2896G>A	p.Ala966Thr	missense_variant	21/22	ENST00000338154.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF8	ENST00000338154.11	c.2896G>A	p.Ala966Thr	missense_variant	21/22	1	NM_015107.3	P2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.18e-7 AC: 1 AN: 1089529 Hom.: 0 Cov.: 31 AF XY: 0.00000280 AC XY: 1 AN XY: 356775

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2022

The c.2896G>A (p.A966T) alteration is located in exon 21 (coding exon 20) of the PHF8 gene. This alteration results from a G to A substitution at nucleotide position 2896, causing the alanine (A) at amino acid position 966 to be replaced by a threonine (T). The PHF8 c.2896G>A alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. 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	0.086
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	17
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.97	N;N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.83	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.12	.;B;.
Vest4		0.068
MutPred		0.14		.;Gain of phosphorylation at A1002 (P = 0.0405);.;
MVP		0.27
MPC		1.5
ClinPred		0.61	D
GERP RS		4.2
Varity_R		0.099
gMVP		0.29

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: rs1557083035; hg19: chrX-53966703;