6-63684465-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001370348.2(PHF3):c.743T>G(p.Val248Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PHF3 NM_001370348.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07

Genes affected

PHF3 (HGNC:8921): (PHD finger protein 3) This gene encodes a member of a PHD finger-containing gene family. This gene may function as a transcription factor and may be involved in glioblastomas development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13061759).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHF3	NM_001370348.2	c.743T>G	p.Val248Gly	missense_variant	4/16	ENST00000262043.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHF3	ENST00000262043.8	c.743T>G	p.Val248Gly	missense_variant	4/16	5	NM_001370348.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461144 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

May 24, 2023

The c.743T>G (p.V248G) alteration is located in exon 3 (coding exon 3) of the PHF3 gene. This alteration results from a T to G substitution at nucleotide position 743, causing the valine (V) at amino acid position 248 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	21
Dann	Benign	0.58
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.61	T;T;T;.;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N;N;N;N;D;N
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Benign	0.076	T;T;T;D;T;D
Polyphen		0.099, 0.39	.;.;.;B;B;B
Vest4		0.41, 0.32, 0.34
MutPred		0.28		.;.;.;Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);Loss of stability (P = 0.0069);
MVP		0.10
MPC		0.12
ClinPred		0.63	D
GERP RS		4.5
Varity_R		0.22
gMVP		0.21

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: rs777077465; hg19: chr6-64394366;