NM_015963.6:c.1319G>C

Variant names:

• chr2-241606395-C-G
• rs751800435
• NM_015963.6:c.1319G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015963.6(THAP4):​c.1319G>C​(p.Gly440Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000275 in 1,600,984 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. G440R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: THAP4 NM_015963.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015963.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THAP4	NM_015963.6	MANE Select	c.1319G>C	p.Gly440Ala	missense	Exon 3 of 6	NP_057047.4
	THAP4	NM_001164356.2		c.83G>C	p.Gly28Ala	missense	Exon 2 of 5	NP_001157828.1	Q8WY91-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THAP4	ENST00000407315.6	TSL:1 MANE Select	c.1319G>C	p.Gly440Ala	missense	Exon 3 of 6	ENSP00000385006.1	Q8WY91-1
	THAP4	ENST00000402136.5	TSL:1	c.83G>C	p.Gly28Ala	missense	Exon 2 of 5	ENSP00000385931.1	Q8WY91-2
	THAP4	ENST00000863246.1		c.1319G>C	p.Gly440Ala	missense	Exon 3 of 6	ENSP00000533305.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152038 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000617 AC: 14 AN: 226928 AF XY: 0.0000570

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000619

Gnomad ASJ exome AF: 0.000737

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000395

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.0000283 AC: 41 AN: 1448946 Hom.: 0 Cov.: 31 AF XY: 0.0000292 AC XY: 21 AN XY: 719546

African (AFR) AF: 0.00 AC: 0 AN: 33198

American (AMR) AF: 0.0000932 AC: 4 AN: 42908

Ashkenazi Jewish (ASJ) AF: 0.000814 AC: 21 AN: 25794

East Asian (EAS) AF: 0.00 AC: 0 AN: 39096

South Asian (SAS) AF: 0.00 AC: 0 AN: 84016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52410

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.00000723 AC: 8 AN: 1105908

Other (OTH) AF: 0.000117 AC: 7 AN: 59860

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152038 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74260

African (AFR) AF: 0.0000242 AC: 1 AN: 41382

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000578 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.27
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.030	D
Polyphen		0.99	D
Vest4		0.61
MutPred		0.73		Loss of disorder (P = 0.1398)
MVP		0.95
MPC		1.4
ClinPred		0.72	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.86
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs751800435; hg19: chr2-242545810;