chr9-120869922-G-T

Position:

• chr9-120869922-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_015651.3(PHF19):​c.388C>A​(p.Pro130Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHF19 NM_015651.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.97

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PHF19
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF19	NM_015651.3	c.388C>A	p.Pro130Thr	missense_variant	5/15	ENST00000373896.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF19	ENST00000373896.8	c.388C>A	p.Pro130Thr	missense_variant	5/15	2	NM_015651.3	P1
PHF19	ENST00000616568.5	c.445C>A	p.Pro149Thr	missense_variant	5/15	1
PHF19	ENST00000312189.10	c.388C>A	p.Pro130Thr	missense_variant	5/5	1
PHF19	ENST00000436309.5	c.388C>A	p.Pro130Thr	missense_variant	5/6	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.388C>A (p.P130T) alteration is located in exon 5 (coding exon 4) of the PHF19 gene. This alteration results from a C to A substitution at nucleotide position 388, causing the proline (P) at amino acid position 130 to be replaced by a threonine (T). 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
Sift4G	Pathogenic	0.0	D;D;.;D
Polyphen		1.0	.;D;.;D
Vest4		0.90
MutPred		0.72		.;Gain of catalytic residue at P130 (P = 0.0568);Gain of catalytic residue at P130 (P = 0.0568);Gain of catalytic residue at P130 (P = 0.0568);
MVP		0.77
MPC		2.2
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.85

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

LitVar

Other links and lift over

dbSNP: rs907039928; hg19: chr9-123632200;