8-132825369-A-C

Variant names:

• chr8-132825369-A-C
• rs771267278
• NM_016018.5:c.1742A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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

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]

ACMG classification

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Sel.	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.: 32

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1344156 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 665250

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

African (AFR) AF: 0.00 AC: 0 AN: 28688

American (AMR) AF: 0.00 AC: 0 AN: 28178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23354

East Asian (EAS) AF: 0.00 AC: 0 AN: 35570

South Asian (SAS) AF: 0.00 AC: 0 AN: 74474

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5294

European-Non Finnish (NFE) AF: 0.00000191 AC: 2 AN: 1045648

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 32

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	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.048
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.13	T
Polyphen		0.0	B
Vest4		0.27
MutPred		0.12		Gain of relative solvent accessibility (P = 0.0098)
MVP		0.068
MPC		0.48
ClinPred		0.28	T
GERP RS		3.0
Varity_R		0.15
gMVP		0.37
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs771267278; hg19: chr8-133837614;