chr17-79834258-C-A

Variant names:

• chr17-79834258-C-A
• rs768529966
• NM_003655.3:c.1384G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B.

Score: 2 - Uncertain Significance

2

PM2

The NM_003655.3(CBX4):​c.1384G>T​(p.Val462Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,956 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V462I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CBX4 NM_003655.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBX4	NM_003655.3	c.1384G>T	p.Val462Phe	missense_variant	Exon 5 of 5	ENST00000269397.9	NP_003646.2
CBX4	XM_011525399.3	c.1186G>T	p.Val396Phe	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	c.1384G>T	p.Val462Phe	missense_variant	Exon 5 of 5	1	NM_003655.3	ENSP00000269397.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452956 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 722202

African (AFR) AF: 0.00 AC: 0 AN: 33134

American (AMR) AF: 0.00 AC: 0 AN: 43702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25758

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.00 AC: 0 AN: 85564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1108328

Other (OTH) AF: 0.00 AC: 0 AN: 59938

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.22
Sift	Uncertain	0.010	D
Sift4G	Benign	0.29	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.22		Loss of sheet (P = 0.1398);
MVP		0.82
MPC		2.1
ClinPred		0.85	D
GERP RS		3.8
Varity_R		0.46
gMVP		0.52

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: rs768529966; hg19: chr17-77808057;