rs188675529

Variant names:

• chr16-67842794-C-G
• rs188675529
• NM_020457.3:c.240C>G

Your query was ambiguous. Multiple possible variants found:

• chr16-67842794-C-G
• chr16-67842794-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_020457.3(THAP11):​c.240C>G​(p.Phe80Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. F80F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: THAP11 NM_020457.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 2.21
• Publications: 8 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: Likely_pathogenic. The variant received 7 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.904
• PP5: Variant 16-67842794-C-G is Pathogenic according to our data. Variant chr16-67842794-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 393304.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THAP11	NM_020457.3	c.240C>G	p.Phe80Leu	missense_variant	Exon 1 of 1	ENST00000303596.3	NP_065190.2
CENPT	NM_025082.4	c.-492+4607G>C		intron_variant	Intron 1 of 15	ENST00000562787.6	NP_079358.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THAP11	ENST00000303596.3	c.240C>G	p.Phe80Leu	missense_variant	Exon 1 of 1	6	NM_020457.3	ENSP00000304689.1
CENPT	ENST00000562787.6	c.-492+4607G>C		intron_variant	Intron 1 of 15	2	NM_025082.4	ENSP00000457810.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic acidemia with homocystinuria, type cblX Pathogenic:1

Dec 07, 2016

Shaikh Laboratory, University of Colorado

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

A patient who presented with phenotypic features that overlap cblX, but did not have any mutations in either MMACHC or HCFC. Using ACMG standards and guidelines for the interpretation of sequence variants (PMID: 25741868). PS3, PM2 PP2, PP3. -

Methylmalonic aciduria and homocystinuria, cb1L type Pathogenic:1

Dec 04, 2024

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Disorders of Intracellular Cobalamin Metabolism Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.2
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.014	D
Sift4G	Benign	0.49	T
Polyphen		1.0	D
Vest4		0.64
MutPred		0.67		Gain of sheet (P = 0.0827);
MVP		1.0
MPC		1.3
ClinPred		0.99	D
GERP RS		3.5
PromoterAI		0.19	Neutral
Varity_R		0.67
gMVP		0.98
Mutation Taster		=14/86	disease causing (ClinVar)

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: rs188675529; hg19: chr16-67876697;