2-241602982-C-A

Variant names:

• chr2-241602982-C-A
• NM_015963.6:c.1498G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015963.6(THAP4):​c.1498G>T​(p.Ala500Ser) 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: 33)
• Consequence: THAP4 NM_015963.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.69

Genes affected

THAP4 (HGNC:23187): (THAP domain containing 4) Enables several functions, including heme binding activity; identical protein binding activity; and peroxynitrite isomerase activity. Involved in nitrate metabolic process and tyrosine metabolic process. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP4	NM_015963.6	c.1498G>T	p.Ala500Ser	missense_variant	Exon 4 of 6	ENST00000407315.6	NP_057047.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THAP4	ENST00000407315.6	c.1498G>T	p.Ala500Ser	missense_variant	Exon 4 of 6	1	NM_015963.6	ENSP00000385006.1
THAP4	ENST00000402136.5	c.262G>T	p.Ala88Ser	missense_variant	Exon 3 of 5	1		ENSP00000385931.1
THAP4	ENST00000402545.5	c.262G>T	p.Ala88Ser	missense_variant	Exon 3 of 5	5		ENSP00000384352.1
THAP4	ENST00000497486.1	n.13G>T		non_coding_transcript_exon_variant	Exon 1 of 4	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1498G>T (p.A500S) alteration is located in exon 4 (coding exon 4) of the THAP4 gene. This alteration results from a G to T substitution at nucleotide position 1498, causing the alanine (A) at amino acid position 500 to be replaced by a serine (S). 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	0.26
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	.;T;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.8	.;L;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Pathogenic	0.68
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.072	B;D;.
Vest4		0.75
MutPred		0.76		.;Gain of disorder (P = 0.0502);.;
MVP		0.91
MPC		0.93
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-242542397;