1-113705913-C-T

Position:

• chr1-113705913-C-T

Variant summary

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

The NM_001323043.2(PHTF1):​c.1648G>A​(p.Val550Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PHTF1 NM_001323043.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45

Genes affected

PHTF1 (HGNC:8939): (putative homeodomain transcription factor 1) Predicted to be located in cis-Golgi network and endoplasmic reticulum membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHTF1	NM_001323043.2	c.1648G>A	p.Val550Met	missense_variant	13/19	ENST00000369604.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHTF1	ENST00000369604.6	c.1648G>A	p.Val550Met	missense_variant	13/19	5	NM_001323043.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Feb 28, 2024

The c.1648G>A (p.V550M) alteration is located in exon 12 (coding exon 12) of the PHTF1 gene. This alteration results from a G to A substitution at nucleotide position 1648, causing the valine (V) at amino acid position 550 to be replaced by a methionine (M). 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	0.97
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;.;D;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;.;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.65	D;D;D;D;D
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Uncertain	2.5	M;.;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;.;D;D
Vest4		0.91
MutPred		0.29		Gain of phosphorylation at T554 (P = 0.166);.;.;Gain of phosphorylation at T554 (P = 0.166);Gain of phosphorylation at T554 (P = 0.166);
MVP		0.43
MPC		0.64
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.62
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs911931113; hg19: chr1-114248535; COSMIC: COSV100760001;