rs77581173

Variant names:

• chrX-54014554-G-A
• rs77581173
• NM_015107.3:c.606C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-54014554-G-A
• chrX-54014554-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BA1

The NM_015107.3(PHF8):​c.606C>T​(p.Asn202Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,198,351 control chromosomes in the GnomAD database, including 50 homozygotes. There are 779 hemizygotes in GnomAD. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (4 hom., 112 hem., cov: 22)
  • Exomes 𝑓: 0.0019 (46 hom. 667 hem.)
• Consequence: PHF8 NM_015107.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.00200
• Publications: 3 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.

• BP6: Variant X-54014554-G-A is Benign according to our data. Variant chrX-54014554-G-A is described in ClinVar as Benign. ClinVar VariationId is 129888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.002 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0621 is higher than 0.05.

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.606C>T	p.Asn202Asn	synonymous	Exon 7 of 22	NP_055922.1	Q9UPP1-2
	PHF8	NM_001184896.1		c.714C>T	p.Asn238Asn	synonymous	Exon 7 of 22	NP_001171825.1	Q9UPP1-1
	PHF8	NM_001441096.1		c.714C>T	p.Asn238Asn	synonymous	Exon 7 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.606C>T	p.Asn202Asn	synonymous	Exon 7 of 22	ENSP00000338868.6	Q9UPP1-2
	PHF8	ENST00000357988.9	TSL:1	c.714C>T	p.Asn238Asn	synonymous	Exon 7 of 22	ENSP00000350676.5	Q9UPP1-1
	PHF8	ENST00000322659.12	TSL:1	c.606C>T	p.Asn202Asn	synonymous	Exon 7 of 22	ENSP00000319473.8	Q9UPP1-5

Frequencies

GnomAD3 genomes AF: 0.00268 AC: 300 AN: 111767 Hom.: 4 Cov.: 22

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000573

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0687

Gnomad SAS AF: 0.00369

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00600

GnomAD2 exomes AF: 0.00605 AC: 1094 AN: 180762 AF XY: 0.00554

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0745

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000124

Gnomad OTH exome AF: 0.00379

GnomAD4 exome AF: 0.00192 AC: 2089 AN: 1086530 Hom.: 46 Cov.: 28 AF XY: 0.00189 AC XY: 667 AN XY: 352422

African (AFR) AF: 0.000610 AC: 16 AN: 26211

American (AMR) AF: 0.0000569 AC: 2 AN: 35127

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19300

East Asian (EAS) AF: 0.0568 AC: 1713 AN: 30144

South Asian (SAS) AF: 0.00188 AC: 101 AN: 53658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40438

Middle Eastern (MID) AF: 0.000248 AC: 1 AN: 4037

European-Non Finnish (NFE) AF: 0.0000216 AC: 18 AN: 831899

Other (OTH) AF: 0.00521 AC: 238 AN: 45716

GnomAD4 genome AF: 0.00269 AC: 301 AN: 111821 Hom.: 4 Cov.: 22 AF XY: 0.00329 AC XY: 112 AN XY: 34011

African (AFR) AF: 0.00104 AC: 32 AN: 30842

American (AMR) AF: 0.000573 AC: 6 AN: 10476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.0692 AC: 244 AN: 3525

South Asian (SAS) AF: 0.00370 AC: 10 AN: 2702

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6059

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53148

Other (OTH) AF: 0.00592 AC: 9 AN: 1521

Alfa AF: 0.00140 Hom.: 24

Bravo AF: 0.00332

ClinVar

ClinVar submissions

Significance: 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.4
DANN	Benign	0.73
PhyloP100		-0.0020
PromoterAI		0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs77581173; hg19: chrX-54040987; COSMIC: COSV57678176; COSMIC: COSV57678176;