NM_020457.3:c.257A>G

Variant names:

• chr16-67842811-A-G
• rs922982889
• NM_020457.3:c.257A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_020457.3(THAP11):​c.257A>G​(p.Asn86Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,930 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: THAP11 NM_020457.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.30
• Publications: 0 publications found

Genes affected

THAP11 (HGNC:23194): (THAP domain containing 11) The protein encoded by this gene contains a THAP domain, which is a conserved DNA-binding domain that has striking similarity to the site-specific DNA-binding domain (DBD) of Drosophila P element transposases. [provided by RefSeq, Jul 2008]

CENPT (HGNC:25787): (centromere protein T) The centromere is a specialized chromatin domain, present throughout the cell cycle, that acts as a platform on which the transient assembly of the kinetochore occurs during mitosis. All active centromeres are characterized by the presence of long arrays of nucleosomes in which CENPA (MIM 117139) replaces histone H3 (see MIM 601128). CENPT is an additional factor required for centromere assembly (Foltz et al., 2006 [PubMed 16622419]).[supplied by OMIM, Mar 2008]

CENPT Gene-Disease associations (from GenCC):

• short stature and microcephaly with genital anomalies

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.1522 (below the threshold of 3.09). Trascript score misZ: 2.3464 (below the threshold of 3.09). GenCC associations: The gene is linked to methylmalonic aciduria and homocystinuria.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020457.3. 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
	THAP11	NM_020457.3	MANE Select	c.257A>G	p.Asn86Ser	missense	Exon 1 of 1	NP_065190.2
	CENPT	NM_025082.4	MANE Select	c.-492+4590T>C		intron	N/A	NP_079358.3	Q96BT3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	THAP11	ENST00000303596.3	TSL:6 MANE Select	c.257A>G	p.Asn86Ser	missense	Exon 1 of 1	ENSP00000304689.1	Q96EK4
	CENPT	ENST00000562787.6	TSL:2 MANE Select	c.-492+4590T>C		intron	N/A	ENSP00000457810.1	Q96BT3-1
	CENPT	ENST00000969291.1		c.-635+4769T>C		intron	N/A	ENSP00000639350.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 151930 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 241938 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458930 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725882

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 86084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5356

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111384

Other (OTH) AF: 0.0000166 AC: 1 AN: 60264

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 151930 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74226

African (AFR) AF: 0.00 AC: 0 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000359 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.0	N
PhyloP100		8.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.27
MVP		0.96
MPC		0.93
ClinPred		0.91	D
GERP RS		5.4
PromoterAI		0.052	Neutral
Varity_R		0.32
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs922982889; hg19: chr16-67876714;