11-134152972-C-A

Variant names:

• chr11-134152972-C-A
• rs147905924
• NM_015261.3:c.4469G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015261.3(NCAPD3):​c.4469G>T​(p.Arg1490Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1490Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NCAPD3 NM_015261.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.38
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3620171).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015261.3. 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.4469G>T	p.Arg1490Leu	missense	Exon 35 of 35	NP_056076.1	P42695
	NCAPD3	NM_001372068.1		c.4427G>T	p.Arg1476Leu	missense	Exon 35 of 35	NP_001358997.1	A0A8I5KT00
	NCAPD3	NM_001372069.1		c.4055G>T	p.Arg1352Leu	missense	Exon 34 of 34	NP_001358998.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAPD3	ENST00000534548.7	TSL:1 MANE Select	c.4469G>T	p.Arg1490Leu	missense	Exon 35 of 35	ENSP00000433681.3	P42695
	NCAPD3	ENST00000525964.7	TSL:1	n.*2111G>T		non_coding_transcript_exon	Exon 36 of 36	ENSP00000431612.2	E9PKK4
	NCAPD3	ENST00000525964.7	TSL:1	n.*2111G>T		3_prime_UTR	Exon 36 of 36	ENSP00000431612.2	E9PKK4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418166 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 700370

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31956

American (AMR) AF: 0.0000254 AC: 1 AN: 39322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23330

East Asian (EAS) AF: 0.00 AC: 0 AN: 39240

South Asian (SAS) AF: 0.00 AC: 0 AN: 78290

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5460

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090012

Other (OTH) AF: 0.00 AC: 0 AN: 58460

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	0.060
Eigen_PC	Benign	0.045
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.097
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.027	D
Polyphen		0.70	P
Vest4		0.51
MutPred		0.32		Loss of methylation at K1495 (P = 0.0343)
MVP		0.35
MPC		0.33
ClinPred		0.85	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.44
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147905924; hg19: chr11-134022867;