Genetic Variant NM_024672.6:c.1182C>A (chr4-82917394-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024672.6(THAP9):c.1182C>A(p.Asp394Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,536 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: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

THAP9
NM_024672.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0710

Variant links:

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]

THAP9 links:

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]

LIN54 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.06406754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP9	NM_024672.6 link	c.1182C>A	p.Asp394Glu	missense_variant	Exon 5 of 5	ENST00000302236.10	NP_078948.3	Q9H5L6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
THAP9	ENST00000302236.10 link	c.1182C>A	p.Asp394Glu	missense_variant	Exon 5 of 5	1	NM_024672.6	ENSP00000305533.5	Q9H5L6
THAP9	ENST00000505901.1 link	n.*939C>A		non_coding_transcript_exon_variant	Exon 6 of 6	2		ENSP00000425966.1	F2Z371
THAP9	ENST00000505901.1 link	n.*939C>A		3_prime_UTR_variant	Exon 6 of 6	2		ENSP00000425966.1	F2Z371
LIN54	ENST00000505905.1 link	n.305-3953G>T		intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461536

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727052

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1182C>A (p.D394E) alteration is located in exon 5 (coding exon 5) of the THAP9 gene. This alteration results from a C to A substitution at nucleotide position 1182, causing the aspartic acid (D) at amino acid position 394 to be replaced by a glutamic acid (E). 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

0.098

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.0027

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.59

M_CAP

Benign

0.046

MetaRNN

Benign

0.064

MetaSVM

Benign

-0.60

MutationAssessor

Benign

0.27

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.76

REVEL

Uncertain

0.31

Sift

Benign

0.20

Sift4G

Benign

0.064

Polyphen

0.0070

Vest4

0.030

MutPred

0.25

Loss of sheet (P = 0.0817);

MVP

0.29

MPC

0.28

ClinPred

0.037

GERP RS

0.60

Varity_R

0.028

gMVP

0.13

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over