rs188675529

chr16-67842794-C-Gchr16-67842794-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 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:1 O:1
• Conservation: PhyloP100: 2.21

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 393304.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THAP11	NM_020457.3	c.240C>G	p.Phe80Leu	missense_variant	1/1	ENST00000303596.3
CENPT	NM_025082.4	c.-492+4607G>C		intron_variant		ENST00000562787.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THAP11	ENST00000303596.3	c.240C>G	p.Phe80Leu	missense_variant	1/1		NM_020457.3	P1
CENPT	ENST00000562787.6	c.-492+4607G>C		intron_variant		2	NM_025082.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonic acidemia with homocystinuria, type cblX Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Shaikh Laboratory, University of Colorado

Dec 07, 2016

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. -

Disorders of Intracellular Cobalamin Metabolism Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

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
MutationTaster	Benign	1.0	D;D
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
Varity_R		0.67
gMVP		0.98

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: rs188675529; hg19: chr16-67876697;