11-134153011-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PVS1_StrongBS1_Supporting

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

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
microcephaly 22, primary, autosomal recessive
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

NCAPD3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.65050507 fraction of the gene.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000466 (71/152302) while in subpopulation AFR AF = 0.00159 (66/41574). AF 95% confidence interval is 0.00128. There are 1 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372068.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NCAPD3	NM_015261.3	MANE Select	c.4430G>C	p.Arg1477Thr	missense	Exon 35 of 35	NP_056076.1	P42695
NCAPD3	NM_001372069.1		c.4016G>C	p.Arg1339Thr	missense	Exon 34 of 34	NP_001358998.1
NCAPD3	NM_001372070.1		c.4016G>C	p.Arg1339Thr	missense	Exon 37 of 37	NP_001358999.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NCAPD3	ENST00000534548.7	TSL:1 MANE Select	c.4430G>C	p.Arg1477Thr	missense	Exon 35 of 35	ENSP00000433681.3	P42695
NCAPD3	ENST00000525964.7	TSL:1	n.*2072G>C		non_coding_transcript_exon	Exon 36 of 36	ENSP00000431612.2	E9PKK4
NCAPD3	ENST00000525964.7	TSL:1	n.*2072G>C		3_prime_UTR	Exon 36 of 36	ENSP00000431612.2	E9PKK4

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

GnomAD2 exomes

AF:

0.000159

AC:

AN:

238978

AF XY:

0.000109

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 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

African (AFR)

AF:

0.00150

AC:

AN:

32754

American (AMR)

AF:

0.000210

AC:

AN:

42774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24924

East Asian (EAS)

AF:

0.00

AC:

AN:

39348

South Asian (SAS)

AF:

0.00

AC:

AN:

83274

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52890

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1099546

Other (OTH)

AF:

0.000118

AC:

AN:

59324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

AF:

0.000466

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00159

AC:

AN:

41574

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68024

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

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

PhyloP100

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

Mutation Taster

=79/21

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over