11-134153015-C-A

Variant names:

• chr11-134153015-C-A
• rs768995468
• NM_015261.3:c.4426G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015261.3(NCAPD3):​c.4426G>T​(p.Ala1476Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. A1476T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NCAPD3 NM_015261.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.864
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.4426G>T	p.Ala1476Ser	missense	Exon 35 of 35	NP_056076.1	P42695
	NCAPD3	NM_001372069.1		c.4012G>T	p.Ala1338Ser	missense	Exon 34 of 34	NP_001358998.1
	NCAPD3	NM_001372070.1		c.4012G>T	p.Ala1338Ser	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.4426G>T	p.Ala1476Ser	missense	Exon 35 of 35	ENSP00000433681.3	P42695
	NCAPD3	ENST00000525964.7	TSL:1	n.*2068G>T		non_coding_transcript_exon	Exon 36 of 36	ENSP00000431612.2	E9PKK4
	NCAPD3	ENST00000525964.7	TSL:1	n.*2068G>T		3_prime_UTR	Exon 36 of 36	ENSP00000431612.2	E9PKK4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1440228 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 713312

African (AFR) AF: 0.00 AC: 0 AN: 32790

American (AMR) AF: 0.00 AC: 0 AN: 42786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24920

East Asian (EAS) AF: 0.00 AC: 0 AN: 39346

South Asian (SAS) AF: 0.00 AC: 0 AN: 83202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52882

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099344

Other (OTH) AF: 0.00 AC: 0 AN: 59332

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.86
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.023
Sift	Benign	0.14	T
Sift4G	Benign	0.30	T
Polyphen		0.61	P
Vest4		0.087
MutPred		0.16		Gain of relative solvent accessibility (P = 0.0023)
MVP		0.26
MPC		0.13
ClinPred		0.36	T
GERP RS		3.7
Varity_R		0.030
gMVP		0.34
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs768995468; hg19: chr11-134022910; COSMIC: COSV100137873; COSMIC: COSV100137873;