rs148215758

Positions:

• chrX-54017674-A-C
• chrX-54017674-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015107.3(PHF8):​c.441T>G​(p.Val147Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,206,266 control chromosomes in the GnomAD database, including 446 homozygotes. There are 11,694 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (34 hom., 727 hem., cov: 23)
  • Exomes 𝑓: 0.031 (412 hom. 10967 hem.)
• Consequence: PHF8 NM_015107.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00800

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]

PHF8 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-54017674-A-C is Benign according to our data. Variant chrX-54017674-A-C is described in ClinVar as [Benign]. Clinvar id is 129890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-54017674-A-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.008 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0229 (2556/111843) while in subpopulation NFE AF= 0.034 (1805/53145). AF 95% confidence interval is 0.0327. There are 34 homozygotes in gnomad4. There are 727 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 34 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHF8	NM_015107.3	c.441T>G	p.Val147Val	synonymous_variant	5/22	ENST00000338154.11	NP_055922.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PHF8	ENST00000338154.11	c.441T>G	p.Val147Val	synonymous_variant	5/22	1	NM_015107.3	ENSP00000338868.6

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 2560 AN: 111789 Hom.: 34 Cov.: 23 AF XY: 0.0214 AC XY: 728 AN XY: 33945

Gnomad AFR AF: 0.00468

Gnomad AMI AF: 0.0294

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0100

Gnomad FIN AF: 0.0448

Gnomad MID AF: 0.0464

Gnomad NFE AF: 0.0340

Gnomad OTH AF: 0.0245

GnomAD3 exomes AF: 0.0259 AC: 4745 AN: 183004 Hom.: 50 AF XY: 0.0255 AC XY: 1722 AN XY: 67454

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0112

Gnomad FIN exome AF: 0.0514

Gnomad NFE exome AF: 0.0373

Gnomad OTH exome AF: 0.0281

GnomAD4 exome AF: 0.0311 AC: 34036 AN: 1094423 Hom.: 412 Cov.: 29 AF XY: 0.0305 AC XY: 10967 AN XY: 360047

Gnomad4 AFR exome AF: 0.00330

Gnomad4 AMR exome AF: 0.0126

Gnomad4 ASJ exome AF: 0.0200

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.0492

Gnomad4 NFE exome AF: 0.0347

Gnomad4 OTH exome AF: 0.0263

GnomAD4 genome AF: 0.0229 AC: 2556 AN: 111843 Hom.: 34 Cov.: 23 AF XY: 0.0214 AC XY: 727 AN XY: 34009

Gnomad4 AFR AF: 0.00464

Gnomad4 AMR AF: 0.0199

Gnomad4 ASJ AF: 0.0136

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00970

Gnomad4 FIN AF: 0.0448

Gnomad4 NFE AF: 0.0340

Gnomad4 OTH AF: 0.0235

Alfa AF: 0.0289 Hom.: 217

Bravo AF: 0.0201

EpiCase AF: 0.0379

EpiControl AF: 0.0351

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 05, 2013

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 07, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	9.8
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs148215758; hg19: chrX-54044107;