11-134153011-C-T

Variant names:

• chr11-134153011-C-T
• rs141510296
• NM_015261.3:c.4430G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001372068.1(NCAPD3):​c.4389-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NCAPD3 NM_001372068.1 splice_acceptor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.48
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAPD3	NM_015261.3	MANE Select	c.4430G>A	p.Arg1477Lys	missense	Exon 35 of 35	NP_056076.1	P42695
	NCAPD3	NM_001372069.1		c.4016G>A	p.Arg1339Lys	missense	Exon 34 of 34	NP_001358998.1
	NCAPD3	NM_001372070.1		c.4016G>A	p.Arg1339Lys	missense	Exon 37 of 37	NP_001358999.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAPD3	ENST00000534548.7	TSL:1 MANE Select	c.4430G>A	p.Arg1477Lys	missense	Exon 35 of 35	ENSP00000433681.3	P42695
	NCAPD3	ENST00000525964.7	TSL:1	n.*2072G>A		non_coding_transcript_exon	Exon 36 of 36	ENSP00000431612.2	E9PKK4
	NCAPD3	ENST00000525964.7	TSL:1	n.*2072G>A		3_prime_UTR	Exon 36 of 36	ENSP00000431612.2	E9PKK4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440462 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 713502

African (AFR) AF: 0.00 AC: 0 AN: 32756

American (AMR) AF: 0.00 AC: 0 AN: 42774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39348

South Asian (SAS) AF: 0.00 AC: 0 AN: 83274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52890

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1099546

Other (OTH) AF: 0.00 AC: 0 AN: 59324

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0049	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		2.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.096
Sift	Benign	0.045	D
Sift4G	Benign	0.28	T
Polyphen		0.85	P
Vest4		0.26
MutPred		0.18		Loss of stability (P = 0.0165)
MVP		0.38
MPC		0.10
ClinPred		0.80	D
GERP RS		5.6
Varity_R		0.087
gMVP		0.34
Mutation Taster		=85/15	polymorphism

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: rs141510296; hg19: chr11-134022906;