Variant 11-134153011-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_001372068.1(NCAPD3):c.4389-1G>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000086 in 1,592,762 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00047 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

NCAPD3
NM_001372068.1 splice_acceptor, intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.48

Variant links:

Genes affected

NCAPD3 (HGNC:28952): (non-SMC condensin II complex subunit D3) Condensin complexes I and II play essential roles in mitotic chromosome assembly and segregation. Both condensins contain 2 invariant structural maintenance of chromosome (SMC) subunits, SMC2 (MIM 605576) and SMC4 (MIM 605575), but they contain different sets of non-SMC subunits. NCAPD3 is 1 of 3 non-SMC subunits that define condensin II (Ono et al., 2003 [PubMed 14532007]).[supplied by OMIM, Mar 2008]

NCAPD3 links:

NCAPD3 (HGNC:):

NCAPD3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.6502806 fraction of the gene.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCAPD3	NM_015261.3 linkuse as main transcript	c.4430G>C	p.Arg1477Thr	missense_variant	35/35	ENST00000534548.7	NP_056076.1	P42695

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCAPD3	ENST00000534548.7 linkuse as main transcript	c.4430G>C	p.Arg1477Thr	missense_variant	35/35	1	NM_015261.3	ENSP00000433681.3		P42695

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00157

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00144

GnomAD3 exomes

AF:

0.000159

AC:

AN:

238978

Hom.:

AF XY:

0.000109

AC XY:

AN XY:

128706

show subpopulations

Gnomad AFR exome

AF:

0.00192

Gnomad AMR exome

AF:

0.000153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000364

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000174

GnomAD4 exome

AF:

0.0000458

AC:

AN:

1440460

Hom.:

Cov.:

AF XY:

0.0000392

AC XY:

AN XY:

713502

show subpopulations

Gnomad4 AFR exome

AF:

0.00150

Gnomad4 AMR exome

AF:

0.000210

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.09e-7

Gnomad4 OTH exome

AF:

0.000118

GnomAD4 genome

AF:

0.000466

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00159

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.0000917

Hom.:

Bravo

AF:

0.000608

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2022

The c.4430G>C (p.R1477T) alteration is located in exon 35 (coding exon 35) of the NCAPD3 gene. This alteration results from a G to C substitution at nucleotide position 4430, causing the arginine (R) at amino acid position 1477 to be replaced by a threonine (T). 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

Benign

0.16

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0085

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.78

M_CAP

Benign

0.017

MetaRNN

Benign

0.015

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

REVEL

Benign

0.14

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.050

Polyphen

0.99

Vest4

0.50

MVP

0.48

MPC

0.43

ClinPred

0.071

GERP RS

5.6

Varity_R

0.12

gMVP

0.42

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

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