NM_016587.4:c.113G>T

Variant names:

• chr7-26206456-G-T
• rs1784678853
• NM_016587.4:c.113G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016587.4(CBX3):​c.113G>T​(p.Arg38Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R38Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CBX3 NM_016587.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.11
• Publications: 0 publications found

Genes affected

CBX3 (HGNC:1553): (chromobox 3) At the nuclear envelope, the nuclear lamina and heterochromatin are adjacent to the inner nuclear membrane. The protein encoded by this gene binds DNA and is a component of heterochromatin. This protein also can bind lamin B receptor, an integral membrane protein found in the inner nuclear membrane. The dual binding functions of the encoded protein may explain the association of heterochromatin with the inner nuclear membrane. This protein binds histone H3 tails methylated at Lys-9 sites. This protein is also recruited to sites of ultraviolet-induced DNA damage and double-strand breaks. Two transcript variants encoding the same protein but differing in the 5' UTR, have been found for this gene.[provided by RefSeq, Mar 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016587.4. 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
	CBX3	NM_016587.4	MANE Select	c.113G>T	p.Arg38Leu	missense	Exon 3 of 6	NP_057671.2
	CBX3	NM_007276.5		c.113G>T	p.Arg38Leu	missense	Exon 3 of 6	NP_009207.2
	CBX3	NM_001410866.1		c.113G>T	p.Arg38Leu	missense	Exon 3 of 6	NP_001397795.1	B8ZZ43

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBX3	ENST00000396386.7	TSL:1 MANE Select	c.113G>T	p.Arg38Leu	missense	Exon 3 of 6	ENSP00000379670.2	Q13185
	CBX3	ENST00000337620.8	TSL:1	c.113G>T	p.Arg38Leu	missense	Exon 3 of 6	ENSP00000336687.4	Q13185
	CBX3	ENST00000409747.5	TSL:1	c.113G>T	p.Arg38Leu	missense	Exon 3 of 6	ENSP00000387348.1	B8ZZ43

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461634 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727112

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111850

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.026	D
Polyphen		0.047	B
Vest4		0.77
MutPred		0.50		Loss of MoRF binding (P = 0.0298)
MVP		0.85
MPC		1.3
ClinPred		0.99	D
GERP RS		5.8
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.45
Mutation Taster		=30/70	disease causing

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: rs1784678853; hg19: chr7-26246076;