Genetic Variant PHF20L1:p.His581Pro (chr8-132825369-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016018.5(PHF20L1):c.1742A>C(p.His581Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,344,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H581L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

PHF20L1
NM_016018.5 missense, splice_region

Scores

Splicing: ADA: 0.0001194

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.29

Publications

0 publications found

Variant links:

Genes affected

PHF20L1 (HGNC:24280): (PHD finger protein 20 like 1) Predicted to enable metal ion binding activity. Predicted to be involved in histone acetylation and regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of NSL complex. [provided by Alliance of Genome Resources, Apr 2022]

PHF20L1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0925816).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016018.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PHF20L1	NM_016018.5	MANE Select	c.1742A>C	p.His581Pro	missense splice_region	Exon 14 of 21	NP_057102.4
PHF20L1	NM_001438309.1		c.1757A>C	p.His586Pro	missense splice_region	Exon 14 of 21	NP_001425238.1
PHF20L1	NM_001438310.1		c.1754A>C	p.His585Pro	missense splice_region	Exon 14 of 21	NP_001425239.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHF20L1	ENST00000395386.7	TSL:5 MANE Select	c.1742A>C	p.His581Pro	missense splice_region	Exon 14 of 21	ENSP00000378784.2	A8MW92-1
PHF20L1	ENST00000939789.1		c.1757A>C	p.His586Pro	missense splice_region	Exon 14 of 21	ENSP00000609848.1
PHF20L1	ENST00000905699.1		c.1754A>C	p.His585Pro	missense splice_region	Exon 14 of 21	ENSP00000575758.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000149

AC:

AN:

1344156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

665250

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28688

American (AMR)

AF:

0.00

AC:

AN:

28178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23354

East Asian (EAS)

AF:

0.00

AC:

AN:

35570

South Asian (SAS)

AF:

0.00

AC:

AN:

74474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5294

European-Non Finnish (NFE)

AF:

0.00000191

AC:

AN:

1045648

Other (OTH)

AF:

0.00

AC:

AN:

55560

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.027

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.69

M_CAP

Benign

0.0067

MetaRNN

Benign

0.093

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

2.3

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.70

REVEL

Benign

0.048

Sift

Uncertain

0.0020

Sift4G

Benign

0.13

Polyphen

0.0

Vest4

0.27

MutPred

0.12

Gain of relative solvent accessibility (P = 0.0098)

MVP

0.068

MPC

0.48

ClinPred

0.28

GERP RS

3.0

Varity_R

0.15

gMVP

0.37

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.11

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over