Genetic Variant PHTF2:p.Leu250Phe (chr7-77910381-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001366089.1(PHTF2):c.748C>T(p.Leu250Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,460,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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: 0.0000048 ( 0 hom. )

Consequence

PHTF2
NM_001366089.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.50

Variant links:

Genes affected

PHTF2 (HGNC:13411): (putative homeodomain transcription factor 2) Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

PHTF2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.110566765).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein	UniProt
PHTF2	NM_001366089.1 link	c.748C>T	p.Leu250Phe	missense_variant	Exon 8 of 19	NP_001353018.1
PHTF2	NM_001127357.2 link	c.646C>T	p.Leu216Phe	missense_variant	Exon 7 of 18	NP_001120829.1	Q8N3S3-2
PHTF2	NM_001395272.1 link	c.646C>T	p.Leu216Phe	missense_variant	Exon 8 of 19	NP_001382201.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHTF2	ENST00000422959.8 link	c.646C>T	p.Leu216Phe	missense_variant	Exon 8 of 19	5		ENSP00000403042.2		Q8N3S3-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248340

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460810

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726616

show subpopulations

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.646C>T (p.L216F) alteration is located in exon 7 (coding exon 7) of the PHTF2 gene. This alteration results from a C to T substitution at nucleotide position 646, causing the leucine (L) at amino acid position 216 to be replaced by a phenylalanine (F). 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

0.080

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.010

T;.;.;.;.;.;.;T

Eigen

Benign

-0.027

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D;.

M_CAP

Benign

0.0012

MetaRNN

Benign

0.11

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.76

N;.;.;.;.;.;.;N

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.33

.;N;N;N;N;N;N;N

REVEL

Benign

0.072

Sift

Benign

0.61

.;T;T;T;T;T;T;T

Sift4G

Benign

0.74

T;T;T;T;T;T;T;T

Polyphen

0.87

P;B;B;.;.;B;.;P

Vest4

0.12

MutPred

0.48

Gain of helix (P = 0.0199);.;.;.;.;.;.;Gain of helix (P = 0.0199);

MVP

0.27

MPC

0.16

ClinPred

0.32

GERP RS

5.5

Varity_R

0.22

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over