rs897945

Positions:

• chr4-82917109-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024672.6(THAP9):​c.897G>T​(p.Leu299Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.522 in 1,612,860 control chromosomes in the GnomAD database, including 231,111 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.43 (16903 hom., cov: 33)
  • Exomes 𝑓: 0.53 (214208 hom.)
• Consequence: THAP9 NM_024672.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.354

Genes affected

THAP9 (HGNC:23192): (THAP domain containing 9) Enables sequence-specific DNA binding activity and transposase activity. Involved in DNA integration and transposition, DNA-mediated. [provided by Alliance of Genome Resources, Apr 2022]

LIN54 (HGNC:25397): (lin-54 DREAM MuvB core complex component) LIN54 is a component of the LIN, or DREAM, complex, an essential regulator of cell cycle genes (Schmit et al., 2009 [PubMed 19725879]).[supplied by OMIM, Dec 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.9059777E-5).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THAP9	NM_024672.6	c.897G>T	p.Leu299Phe	missense_variant	5/5	ENST00000302236.10	NP_078948.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THAP9	ENST00000302236.10	c.897G>T	p.Leu299Phe	missense_variant	5/5	1	NM_024672.6	ENSP00000305533.5
THAP9	ENST00000505901.1	n.*654G>T		non_coding_transcript_exon_variant	6/6	2		ENSP00000425966.1
THAP9	ENST00000505901.1	n.*654G>T		3_prime_UTR_variant	6/6	2		ENSP00000425966.1
LIN54	ENST00000505905.1	n.305-3668C>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65329 AN: 151986 Hom.: 16889 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.579

Gnomad MID AF: 0.363

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.454

GnomAD3 exomes AF: 0.504 AC: 126049 AN: 250308 Hom.: 35311 AF XY: 0.500 AC XY: 67635 AN XY: 135314

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.704

Gnomad ASJ exome AF: 0.471

Gnomad EAS exome AF: 0.197

Gnomad SAS exome AF: 0.376

Gnomad FIN exome AF: 0.596

Gnomad NFE exome AF: 0.564

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.531 AC: 776387 AN: 1460756 Hom.: 214208 Cov.: 67 AF XY: 0.527 AC XY: 382904 AN XY: 726692

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.696

Gnomad4 ASJ exome AF: 0.466

Gnomad4 EAS exome AF: 0.258

Gnomad4 SAS exome AF: 0.373

Gnomad4 FIN exome AF: 0.599

Gnomad4 NFE exome AF: 0.561

Gnomad4 OTH exome AF: 0.483

GnomAD4 genome AF: 0.430 AC: 65360 AN: 152104 Hom.: 16903 Cov.: 33 AF XY: 0.427 AC XY: 31743 AN XY: 74344

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.583

Gnomad4 ASJ AF: 0.463

Gnomad4 EAS AF: 0.218

Gnomad4 SAS AF: 0.353

Gnomad4 FIN AF: 0.579

Gnomad4 NFE AF: 0.562

Gnomad4 OTH AF: 0.458

Alfa AF: 0.523 Hom.: 45600

Bravo AF: 0.423

TwinsUK AF: 0.572 AC: 2120

ALSPAC AF: 0.577 AC: 2222

ESP6500AA AF: 0.151 AC: 666

ESP6500EA AF: 0.558 AC: 4799

ExAC AF: 0.493 AC: 59889

Asia WGS AF: 0.340 AC: 1182 AN: 3478

EpiCase AF: 0.548

EpiControl AF: 0.543

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.00046	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.000019	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.73	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	2.4	N
REVEL	Benign	0.11
Sift	Benign	0.50	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.91	P
Vest4		0.11
MutPred		0.10		Loss of helix (P = 0.0558);
MPC		0.52
ClinPred		0.012	T
GERP RS		2.9
Varity_R		0.060
gMVP		0.50

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: rs897945; hg19: chr4-83838262; COSMIC: COSV56355919; COSMIC: COSV56355919;