7-26206456-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016587.4(CBX3):​c.113G>A​(p.Arg38Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CBX3 NM_016587.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.11

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

Verdict is Uncertain_significance. Variant got 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
CBX3	NM_016587.4	c.113G>A	p.Arg38Gln	missense_variant	Exon 3 of 6	ENST00000396386.7	NP_057671.2
CBX3	NM_007276.5	c.113G>A	p.Arg38Gln	missense_variant	Exon 3 of 6		NP_009207.2
CBX3	NM_001410866.1	c.113G>A	p.Arg38Gln	missense_variant	Exon 3 of 6		NP_001397795.1
CBX3	XM_005249611.5	c.113G>A	p.Arg38Gln	missense_variant	Exon 3 of 6		XP_005249668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBX3	ENST00000396386.7	c.113G>A	p.Arg38Gln	missense_variant	Exon 3 of 6	1	NM_016587.4	ENSP00000379670.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461634 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727112

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.113G>A (p.R38Q) alteration is located in exon 3 (coding exon 2) of the CBX3 gene. This alteration results from a G to A substitution at nucleotide position 113, causing the arginine (R) at amino acid position 38 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	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;D;D;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.3	L;L;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.8	N;N;D;D;.
REVEL	Uncertain	0.47
Sift	Benign	0.12	T;T;T;T;.
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.0070	B;B;.;D;.
Vest4		0.49
MutPred		0.47		Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);.;
MVP		0.86
MPC		1.1
ClinPred		0.86	D
GERP RS		5.8
Varity_R		0.64
gMVP		0.18

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

Other links and lift over

dbSNP: rs1784678853; hg19: chr7-26246076;