chr14-23557208-T-G

Position:

• chr14-23557208-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_024328.6(THTPA):​c.451T>G​(p.Phe151Val) variant causes a missense change. 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: THTPA NM_024328.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.39

Genes affected

THTPA (HGNC:18987): (thiamine triphosphatase) This gene encodes an enzyme which catalyzes the biosynthesis of thiamine disphophate (vitamin B1) by hydrolysis of thiamine triphosphate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]

ZFHX2-AS1 (HGNC:52658): (ZFHX2 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THTPA	NM_024328.6	c.451T>G	p.Phe151Val	missense_variant	1/2	ENST00000288014.7	NP_077304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THTPA	ENST00000288014.7	c.451T>G	p.Phe151Val	missense_variant	1/2	1	NM_024328.6	ENSP00000288014	P1
ZFHX2-AS1	ENST00000553985.1	n.239-1487T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

May 30, 2024

The c.451T>G (p.F151V) alteration is located in exon 1 (coding exon 1) of the THTPA gene. This alteration results from a T to G substitution at nucleotide position 451, causing the phenylalanine (F) at amino acid position 151 to be replaced by a valine (V). 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	0.86
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.74	.;T
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.4	M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.82		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.56
MPC		0.13
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-24026417;