Genetic Variant NM_003655.3:c.1246G>C (chr17-79834396-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003655.3(CBX4):c.1246G>C(p.Glu416Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000126 in 1,581,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CBX4
NM_003655.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.48

Variant links:

Genes affected

CBX4 (HGNC:1554): (chromobox 4) Enables SUMO binding activity; SUMO ligase activity; and enzyme binding activity. Involved in negative regulation of transcription by RNA polymerase II. Located in nuclear body. Part of PRC1 complex. Implicated in hepatocellular carcinoma. Biomarker of hepatocellular carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

CBX4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBX4	NM_003655.3 link	c.1246G>C	p.Glu416Gln	missense_variant	Exon 5 of 5	ENST00000269397.9	NP_003646.2	O00257-1A0A0S2Z5B2
CBX4	XM_011525399.3 link	c.1048G>C	p.Glu350Gln	missense_variant	Exon 3 of 3		XP_011523701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBX4	ENST00000269397.9 link	c.1246G>C	p.Glu416Gln	missense_variant	Exon 5 of 5	1	NM_003655.3	ENSP00000269397.4		O00257-1

Frequencies

GnomAD3 genomes

AF:

0.00000670

AC:

AN:

149210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

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

GnomAD3 exomes

AF:

0.00000490

AC:

AN:

204162

Hom.:

AF XY:

0.00

AC XY:

AN XY:

113764

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.98e-7

AC:

AN:

1431900

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711766

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.05e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000670

AC:

AN:

149210

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72654

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000198

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1246G>C (p.E416Q) alteration is located in exon 5 (coding exon 5) of the CBX4 gene. This alteration results from a G to C substitution at nucleotide position 1246, causing the glutamic acid (E) at amino acid position 416 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.85

M_CAP

Benign

0.052

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.2

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.2

REVEL

Uncertain

0.33

Sift

Uncertain

0.0020

Sift4G

Benign

0.075

Polyphen

0.79

Vest4

0.27

MutPred

0.18

Gain of MoRF binding (P = 0.0199);

MVP

0.39

MPC

1.2

ClinPred

0.60

GERP RS

4.0

Varity_R

0.30

gMVP

0.42

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

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