chr2-241606396-C-T

Variant names:

• chr2-241606396-C-T
• rs757514473
• NM_015963.6:c.1318G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015963.6(THAP4):​c.1318G>A​(p.Gly440Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000345 in 1,449,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G440A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: THAP4 NM_015963.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.91

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP4	NM_015963.6	c.1318G>A	p.Gly440Arg	missense_variant	Exon 3 of 6	ENST00000407315.6	NP_057047.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THAP4	ENST00000407315.6	c.1318G>A	p.Gly440Arg	missense_variant	Exon 3 of 6	1	NM_015963.6	ENSP00000385006.1
THAP4	ENST00000402136.5	c.82G>A	p.Gly28Arg	missense_variant	Exon 2 of 5	1		ENSP00000385931.1
THAP4	ENST00000402545.5	c.82G>A	p.Gly28Arg	missense_variant	Exon 2 of 5	5		ENSP00000384352.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1449164 Hom.: 0 Cov.: 31 AF XY: 0.00000417 AC XY: 3 AN XY: 719698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000233

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000204 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1318G>A (p.G440R) alteration is located in exon 3 (coding exon 3) of the THAP4 gene. This alteration results from a G to A substitution at nucleotide position 1318, causing the glycine (G) at amino acid position 440 to be replaced by an arginine (R). 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	0.88
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T;T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.0	.;M;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.4	D;D;D;.
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.83
MutPred		0.81		.;Gain of solvent accessibility (P = 0.0789);.;.;
MVP		0.93
MPC		1.5
ClinPred		0.99	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.80
gMVP		0.96

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: rs757514473; hg19: chr2-242545811;