17-79834118-T-TGCCGCCGCCGCCGCCACCGCC

Variant names:

• chr17-79834118-T-TGCCGCCGCCGCCGCCACCGCC
• rs754126884
• NM_003655.3:c.1523_1524insGGCGGTGGCGGCGGCGGCGGC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_003655.3(CBX4):​c.1523_1524insGGCGGTGGCGGCGGCGGCGGC​(p.Ala508_Ala509insAlaValAlaAlaAlaAlaAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,974 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CBX4 NM_003655.3 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.910
• 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: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003655.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBX4	NM_003655.3	c.1523_1524insGGCGGTGGCGGCGGCGGCGGC	p.Ala508_Ala509insAlaValAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 5 of 5	ENST00000269397.9	NP_003646.2
CBX4	XM_011525399.3	c.1325_1326insGGCGGTGGCGGCGGCGGCGGC	p.Ala442_Ala443insAlaValAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 3 of 3		XP_011523701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBX4	ENST00000269397.9	c.1523_1524insGGCGGTGGCGGCGGCGGCGGC	p.Ala508_Ala509insAlaValAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 5 of 5	1	NM_003655.3	ENSP00000269397.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450974 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 720974

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

African (AFR) AF: 0.0000305 AC: 1 AN: 32746

American (AMR) AF: 0.00 AC: 0 AN: 43700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25828

East Asian (EAS) AF: 0.00 AC: 0 AN: 39260

South Asian (SAS) AF: 0.00 AC: 0 AN: 85202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51584

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107158

Other (OTH) AF: 0.00 AC: 0 AN: 59782

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00666416), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.91

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs754126884; hg19: chr17-77807917;