22-21000085-C-G

Variant names:

• chr22-21000085-C-G
• rs759973415
• NM_030573.3:c.725G>C

Variant summary

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

The NM_030573.3(THAP7):​c.725G>C​(p.Arg242Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R242Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: THAP7 NM_030573.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.80
• Publications: 0 publications found

Genes affected

THAP7 (HGNC:23190): (THAP domain containing 7) Enables several functions, including C2H2 zinc finger domain binding activity; histone binding activity; and histone deacetylase binding activity. Involved in negative regulation of histone acetylation and negative regulation of transcription by RNA polymerase II. Located in nuclear membrane and nuclear speck. [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, 0.744

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030573.3. 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
	THAP7	NM_030573.3	MANE Select	c.725G>C	p.Arg242Pro	missense	Exon 4 of 4	NP_085050.2	Q9BT49
	THAP7	NM_001008695.1		c.725G>C	p.Arg242Pro	missense	Exon 5 of 5	NP_001008695.1	Q9BT49

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THAP7	ENST00000215742.9	TSL:1 MANE Select	c.725G>C	p.Arg242Pro	missense	Exon 4 of 4	ENSP00000215742.4	Q9BT49
	THAP7	ENST00000399133.2	TSL:2	c.725G>C	p.Arg242Pro	missense	Exon 5 of 5	ENSP00000382084.2	Q9BT49
	THAP7	ENST00000917978.1		c.569G>C	p.Arg190Pro	missense	Exon 3 of 3	ENSP00000588037.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460416 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 726538

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111888

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.74	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Benign	0.55	N
PhyloP100		1.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.42		Loss of MoRF binding (P = 6e-04)
MVP		0.97
MPC		1.5
ClinPred		0.84	D
GERP RS		4.3
Varity_R		0.56
gMVP		0.83
Mutation Taster		=65/35	polymorphism

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: rs759973415; hg19: chr22-21354374;