16-67842852-G-C

Variant names:

• chr16-67842852-G-C
• rs754275294
• NM_020457.3:c.298G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP2 BP4

The NM_020457.3(THAP11):​c.298G>C​(p.Ala100Pro) variant causes a missense change. In-silico tool predicts a benign 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. A100S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: THAP11 NM_020457.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.05
• Publications: 4 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 0 ACMG points.

• 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, inborn disorder of cobalamin metabolism and transport.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34796655).

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.298G>C	p.Ala100Pro	missense	Exon 1 of 1	NP_065190.2
	CENPT	NM_025082.4	MANE Select	c.-492+4549C>G		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.298G>C	p.Ala100Pro	missense	Exon 1 of 1	ENSP00000304689.1	Q96EK4
	CENPT	ENST00000562787.6	TSL:2 MANE Select	c.-492+4549C>G		intron	N/A	ENSP00000457810.1	Q96BT3-1
	CENPT	ENST00000969291.1		c.-635+4728C>G		intron	N/A	ENSP00000639350.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 150160 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: 0.0000538 AC: 12 AN: 222912 AF XY: 0.0000484

Gnomad AFR exome AF: 0.0000768

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000639

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.89e-7 AC: 1 AN: 1451356 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722152

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 44358

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.00 AC: 0 AN: 86038

European-Finnish (FIN) AF: 0.0000211 AC: 1 AN: 47374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4166

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110560

Other (OTH) AF: 0.00 AC: 0 AN: 59968

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 150160 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73176

African (AFR) AF: 0.00 AC: 0 AN: 40908

American (AMR) AF: 0.00 AC: 0 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 5074

South Asian (SAS) AF: 0.00 AC: 0 AN: 4746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67156

Other (OTH) AF: 0.00 AC: 0 AN: 2058

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		5.0
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.076
Sift	Benign	0.16	T
Sift4G	Benign	0.17	T
Polyphen		0.92	P
Vest4		0.29
MVP		0.85
MPC		1.5
ClinPred		0.16	T
GERP RS		5.4
PromoterAI		-0.044	Neutral
Varity_R		0.39
gMVP		0.68

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: rs754275294; hg19: chr16-67876755; COSMIC: COSV54645570; COSMIC: COSV54645570;