4-75516845-A-G

Position:

• chr4-75516845-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_144721.6(THAP6):​c.154A>G​(p.Ile52Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: THAP6 NM_144721.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

Genes affected

THAP6 (HGNC:23189): (THAP domain containing 6) Predicted to enable DNA binding activity and metal ion binding activity. Located in microtubule cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36871937).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THAP6	NM_144721.6	c.154A>G	p.Ile52Val	missense_variant	3/5	ENST00000311638.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THAP6	ENST00000311638.7	c.154A>G	p.Ile52Val	missense_variant	3/5	1	NM_144721.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

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

Jul 06, 2022

The c.154A>G (p.I52V) alteration is located in exon 3 (coding exon 2) of the THAP6 gene. This alteration results from a A to G substitution at nucleotide position 154, causing the isoleucine (I) at amino acid position 52 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	Benign	0.084
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	15
DANN	Uncertain	0.98
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.013
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.68	T;T;T;.;T;T;T;T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.54	D
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.14	N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.40
Sift	Benign	0.28	T;T;T;T;T;T;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		0.88, 0.0, 0.18	.;.;P;B;B;.;.;.;.;B
Vest4		0.38, 0.29, 0.31, 0.33, 0.34, 0.30, 0.30, 0.29
MutPred		0.40		Gain of ubiquitination at K56 (P = 0.0764);.;.;Gain of ubiquitination at K56 (P = 0.0764);Gain of ubiquitination at K56 (P = 0.0764);Gain of ubiquitination at K56 (P = 0.0764);.;.;.;Gain of ubiquitination at K56 (P = 0.0764);
MVP		0.57
MPC		0.16
ClinPred		0.45	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.094

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: chr4-76442055;