rs782660284

Variant names:

• chrX-53940367-TGAG-T
• rs782660284
• NM_015107.3:c.2796_2798delCTC

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_015107.3(PHF8):​c.2796_2798delCTC​(p.Ser933del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000886 in 1,207,312 control chromosomes in the GnomAD database, including 7 homozygotes. There are 282 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S932S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0050 (2 hom., 136 hem., cov: 22)
  • Exomes 𝑓: 0.00047 (5 hom. 146 hem.)
• Consequence: PHF8 NM_015107.3 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.45
• Publications: 4 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_015107.3
• BP6: Variant X-53940367-TGAG-T is Benign according to our data. Variant chrX-53940367-TGAG-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00495 (550/111003) while in subpopulation AFR AF = 0.017 (519/30557). AF 95% confidence interval is 0.0158. There are 2 homozygotes in GnomAd4. There are 136 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

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.2796_2798delCTC	p.Ser933del	disruptive_inframe_deletion	Exon 21 of 22	NP_055922.1	Q9UPP1-2
	PHF8	NM_001184896.1		c.2904_2906delCTC	p.Ser969del	disruptive_inframe_deletion	Exon 21 of 22	NP_001171825.1	Q9UPP1-1
	PHF8	NM_001441096.1		c.2601_2603delCTC	p.Ser868del	disruptive_inframe_deletion	Exon 20 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.2796_2798delCTC	p.Ser933del	disruptive_inframe_deletion	Exon 21 of 22	ENSP00000338868.6	Q9UPP1-2
	PHF8	ENST00000357988.9	TSL:1	c.2904_2906delCTC	p.Ser969del	disruptive_inframe_deletion	Exon 21 of 22	ENSP00000350676.5	Q9UPP1-1
	PHF8	ENST00000396282.7	TSL:5	c.2796_2798delCTC	p.Ser933del	disruptive_inframe_deletion	Exon 20 of 22	ENSP00000379578.3	H0Y3N9

Frequencies

GnomAD3 genomes AF: 0.00496 AC: 550 AN: 110953 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00231

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00406

GnomAD2 exomes AF: 0.00123 AC: 220 AN: 178336 AF XY: 0.000648

Gnomad AFR exome AF: 0.0155

Gnomad AMR exome AF: 0.000740

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.000474 AC: 520 AN: 1096309 Hom.: 5 AF XY: 0.000404 AC XY: 146 AN XY: 361799

African (AFR) AF: 0.0163 AC: 430 AN: 26382

American (AMR) AF: 0.000771 AC: 27 AN: 35001

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19353

East Asian (EAS) AF: 0.00 AC: 0 AN: 30175

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53723

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40409

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4114

European-Non Finnish (NFE) AF: 0.00000594 AC: 5 AN: 841132

Other (OTH) AF: 0.00122 AC: 56 AN: 46020

GnomAD4 genome AF: 0.00495 AC: 550 AN: 111003 Hom.: 2 Cov.: 22 AF XY: 0.00409 AC XY: 136 AN XY: 33287

African (AFR) AF: 0.0170 AC: 519 AN: 30557

American (AMR) AF: 0.00230 AC: 24 AN: 10420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2630

East Asian (EAS) AF: 0.00 AC: 0 AN: 3520

South Asian (SAS) AF: 0.00 AC: 0 AN: 2610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5985

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 52883

Other (OTH) AF: 0.00401 AC: 6 AN: 1498

Alfa AF: 0.00165 Hom.: 6

Bravo AF: 0.00591

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	PHF8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
Mutation Taster		=76/24	polymorphism (auto)

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: rs782660284; hg19: chrX-53966800;