Genetic Variant CBX3:c.330+3A>G (chr7-26208558-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_016587.4(CBX3):c.330+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0000076 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBX3
NM_016587.4 splice_region, intron

Scores

Splicing: ADA: 0.1958

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 3.20

Variant links:

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]

CBX3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
CBX3	NM_016587.4 link	c.330+3A>G	splice_region_variant, intron_variant	Intron 4 of 5	ENST00000396386.7	NP_057671.2	Q13185A4D177
CBX3	NM_007276.5 link	c.330+3A>G	splice_region_variant, intron_variant	Intron 4 of 5		NP_009207.2	Q13185A4D177
CBX3	NM_001410866.1 link	c.257+3A>G	splice_region_variant, intron_variant	Intron 4 of 5		NP_001397795.1
CBX3	XM_005249611.5 link	c.330+3A>G	splice_region_variant, intron_variant	Intron 4 of 5		XP_005249668.1	Q13185A4D177

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBX3	ENST00000396386.7 link	c.330+3A>G		splice_region_variant, intron_variant	Intron 4 of 5	1	NM_016587.4	ENSP00000379670.2		Q13185

Frequencies

GnomAD3 genomes

AF:

0.00000762

AC:

AN:

131150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000279

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000794

AC:

AN:

1133058

Hom.:

Cov.:

AF XY:

0.00000716

AC XY:

AN XY:

558864

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

26302

Gnomad4 AMR exome

AF:

0.0000347

AC:

AN:

28786

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

16528

Gnomad4 EAS exome

AF:

0.0000810

AC:

AN:

24678

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

69334

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

34966

Gnomad4 NFE exome

AF:

0.00000453

AC:

AN:

883534

Gnomad4 Remaining exome

AF:

0.0000450

AC:

AN:

44450

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000762

AC:

AN:

131272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

64360

show subpopulations

Gnomad4 AFR

AF:

0.0000279

AC:

0.0000278552

AN:

0.0000278552

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Recurrent spontaneous abortion

Uncertain:1

Jan 27, 2020

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=97/3

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.20

dbscSNV1_RF

Benign

0.29

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