Genetic Variant PHF19:p.Met483Leu (chr9-120858240-T-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_015651.3(PHF19):c.1447A>T(p.Met483Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000514 in 1,555,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Consequence

PHF19
NM_015651.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.453

Publications

0 publications found

Variant links:

Genes affected

PHF19 (HGNC:24566): (PHD finger protein 19) Enables methylated histone binding activity. Involved in positive regulation of histone H3-K27 methylation. Colocalizes with ESC/E(Z) complex. [provided by Alliance of Genome Resources, Apr 2022]

PHF19 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017177433).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHF19	NM_015651.3 link	c.1447A>T	p.Met483Leu	missense_variant	Exon 15 of 15	ENST00000373896.8	NP_056466.1	Q5T6S3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHF19	ENST00000373896.8 link	c.1447A>T	p.Met483Leu	missense_variant	Exon 15 of 15	2	NM_015651.3	ENSP00000363003.3		Q5T6S3-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000282

AC:

AN:

212634

AF XY:

0.0000265

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000339

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000499

AC:

AN:

1403754

Hom.:

Cov.:

AF XY:

0.00000725

AC XY:

AN XY:

689906

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32156

American (AMR)

AF:

0.00

AC:

AN:

39506

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22786

East Asian (EAS)

AF:

0.000181

AC:

AN:

38776

South Asian (SAS)

AF:

0.00

AC:

AN:

78550

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50782

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5544

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077820

Other (OTH)

AF:

0.00

AC:

AN:

57834

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000248

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1447A>T (p.M483L) alteration is located in exon 15 (coding exon 14) of the PHF19 gene. This alteration results from a A to T substitution at nucleotide position 1447, causing the methionine (M) at amino acid position 483 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.30

(source)

DANN

Benign

0.84

DEOGEN2

Benign

0.0062

T;.;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.57

T;T;T

M_CAP

Benign

0.0052

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;N

PhyloP100

-0.45

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.080

N;.;N

REVEL

Benign

0.018

Sift

Benign

0.71

T;.;T

Sift4G

Benign

0.91

T;T;T

Polyphen

0.0

.;.;B

Vest4

0.097

MutPred

0.32

.;.;Loss of catalytic residue at M483 (P = 0.0551);

MVP

0.068

MPC

0.87

ClinPred

0.0069

GERP RS

-2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.035

gMVP

0.13

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

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9-120858240-T-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over