X-53940221-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BS1_Supporting

The NM_015107.3(PHF8):c.2945G>A(p.Arg982Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000158 in 1,076,553 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000016 (0 hom. 5 hem.)
• Consequence: PHF8 NM_015107.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.83

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 Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PHF8
• BP4: Computational evidence support a benign effect (MetaRNN=0.13129434).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000158 (17/1076553) while in subpopulation SAS AF= 0.0000779 (4/51363). AF 95% confidence interval is 0.0000262. There are 0 homozygotes in gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF8	NM_015107.3	c.2945G>A	p.Arg982Gln	missense_variant	21/22	ENST00000338154.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF8	ENST00000338154.11	c.2945G>A	p.Arg982Gln	missense_variant	21/22	1	NM_015107.3	P2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000140 AC: 2 AN: 142592 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 43636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000431

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000646

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000158 AC: 17 AN: 1076553 Hom.: 0 Cov.: 31 AF XY: 0.0000143 AC XY: 5 AN XY: 350519

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000315

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000779

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000132

Gnomad4 OTH exome AF: 0.0000221

GnomAD4 genome Cov.: 22

ExAC AF: 0.0000168 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 07, 2023

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Uncertain	24
Dann	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.11
Sift	Uncertain	0.027	D;D;D
Sift4G	Uncertain	0.054	T;D;T
Polyphen		1.0	.;D;.
Vest4		0.16
MutPred		0.21		.;Loss of MoRF binding (P = 0.0299);.;
MVP		0.54
MPC		2.4
ClinPred		0.82	D
GERP RS		5.2
Varity_R		0.31
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs781873999; hg19: chrX-53966654;