rs1557099144

Variant names:

• chrX-53985131-G-GC
• rs1557099144
• NM_015107.3:c.2225dupG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_015107.3(PHF8):​c.2225dupG​(p.Ser742ArgfsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: PHF8 NM_015107.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.587
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability Siderius type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-53985131-G-GC is Pathogenic according to our data. Variant chrX-53985131-G-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 521817.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015107.3. 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
	PHF8	NM_015107.3	MANE Select	c.2225dupG	p.Ser742ArgfsTer26	frameshift	Exon 18 of 22	NP_055922.1	Q9UPP1-2
	PHF8	NM_001184896.1		c.2333dupG	p.Ser778ArgfsTer26	frameshift	Exon 18 of 22	NP_001171825.1	Q9UPP1-1
	PHF8	NM_001441096.1		c.2030dupG	p.Ser677ArgfsTer26	frameshift	Exon 17 of 22	NP_001428025.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHF8	ENST00000338154.11	TSL:1 MANE Select	c.2225dupG	p.Ser742ArgfsTer26	frameshift	Exon 18 of 22	ENSP00000338868.6	Q9UPP1-2
	PHF8	ENST00000357988.9	TSL:1	c.2333dupG	p.Ser778ArgfsTer26	frameshift	Exon 18 of 22	ENSP00000350676.5	Q9UPP1-1
	PHF8	ENST00000322659.12	TSL:1	c.2174dupG	p.Ser725ArgfsTer26	frameshift	Exon 19 of 22	ENSP00000319473.8	Q9UPP1-5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.59
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs1557099144; hg19: chrX-54011564;