7-108564769-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001130475.3(THAP5):c.610A>G(p.Thr204Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: THAP5 NM_001130475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.470

Genes affected

THAP5 (HGNC:23188): (THAP domain containing 5) Enables protease binding activity. Involved in negative regulation of cell cycle and negative regulation of transcription by RNA polymerase II. Located in chromatin and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PNPLA8 (HGNC:28900): (patatin like phospholipase domain containing 8) This gene encodes a member of the patatin-like phospholipase domain containing protein family. Members of this family are phospholipases which catalyze the cleavage of fatty acids from membrane phospholipids. The product of this gene is a calcium-independent phospholipase. Mutations in this gene have been associated with mitochondrial myopathy with lactic acidosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2015]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.065231204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THAP5	NM_001130475.3	c.610A>G	p.Thr204Ala	missense_variant	3/3	ENST00000415914.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THAP5	ENST00000415914.4	c.610A>G	p.Thr204Ala	missense_variant	3/3	1	NM_001130475.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460966 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726716

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Feb 15, 2023

The c.610A>G (p.T204A) alteration is located in exon 3 (coding exon 3) of the THAP5 gene. This alteration results from a A to G substitution at nucleotide position 610, causing the threonine (T) at amino acid position 204 to be replaced by an alanine (A). 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	0.067
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	14
Dann	Benign	0.86
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.55	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.065	T;T
MetaSVM	Uncertain	-0.0044	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.39	N;N
REVEL	Benign	0.21
Sift	Benign	0.31	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.0020	B;.
Vest4		0.014
MutPred		0.22		Loss of glycosylation at T204 (P = 0.0235);.;
MVP		0.26
MPC		0.085
ClinPred		0.079	T
GERP RS		2.1
Varity_R		0.043
gMVP		0.40

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: chr7-108205213;