Genetic Variant CHTOP:p.Thr33Met (chr1-153638327-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_015607.4(CHTOP):c.98C>T(p.Thr33Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CHTOP
NM_015607.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.54

Variant links:

Genes affected

CHTOP (HGNC:24511): (chromatin target of PRMT1) This gene encodes a small nuclear protein that is characterized by an arginine and glycine rich region. This protein may have an important role in the regulation of fetal globin gene expression and in the activation of estrogen-responsive genes. A recent study reported that this protein binds 5-hydroxymethylcytosine (5hmC) and associates with an arginine methyltransferase complex (methylosome), which promotes methylation of arginine 3 of histone H4 (H4R3) and activation of genes involved in glioblastomagenesis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Nov 2015]

CHTOP links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.039893806).

BP6

Variant 1-153638327-C-T is Benign according to our data. Variant chr1-153638327-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2364505.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHTOP	NM_015607.4 link	c.98C>T	p.Thr33Met	missense_variant	Exon 3 of 6	ENST00000368694.8	NP_056422.2	Q9Y3Y2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHTOP	ENST00000368694.8 link	c.98C>T	p.Thr33Met	missense_variant	Exon 3 of 6	1	NM_015607.4	ENSP00000357683.3		Q9Y3Y2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251486

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000547

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 16, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.039

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.0094

.;.;T;.;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.85

D;D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.040

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.97

.;N;N;N;.

PrimateAI

Benign

0.32

PROVEAN

Benign

0.88

.;N;N;N;N

REVEL

Uncertain

0.29

Sift

Benign

0.52

.;T;T;T;T

Sift4G

Benign

0.23

T;T;T;T;T

Polyphen

0.0020, 0.0010

.;B;B;B;.

Vest4

0.20

MutPred

0.23

Gain of catalytic residue at T33 (P = 0.0214);Gain of catalytic residue at T33 (P = 0.0214);Gain of catalytic residue at T33 (P = 0.0214);Gain of catalytic residue at T33 (P = 0.0214);.;

MVP

0.082

MPC

0.65

ClinPred

0.13

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.033

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over