11-134153833-A-G

Variant names:

• chr11-134153833-A-G
• rs94499
• NM_015261.3:c.4253-470T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015261.3(NCAPD3):​c.4253-470T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 186,584 control chromosomes in the GnomAD database, including 5,499 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.24 (4677 hom., cov: 32)
  • Exomes 𝑓: 0.20 (822 hom.)
• Consequence: NCAPD3 NM_015261.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.643
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAPD3	NM_015261.3	MANE Select	c.4253-470T>C		intron	N/A	NP_056076.1
	NCAPD3	NM_001372068.1		c.4253-470T>C		intron	N/A	NP_001358997.1
	NCAPD3	NM_001372065.1		c.4253-470T>C		intron	N/A	NP_001358994.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAPD3	ENST00000534548.7	TSL:1 MANE Select	c.4253-470T>C		intron	N/A	ENSP00000433681.3
	NCAPD3	ENST00000525964.7	TSL:1	n.*1895-470T>C		intron	N/A	ENSP00000431612.2
	NCAPD3	ENST00000525432.2	TSL:3	n.7458T>C		non_coding_transcript_exon	Exon 32 of 35

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37146 AN: 151900 Hom.: 4670 Cov.: 32

Gnomad AFR AF: 0.293

Gnomad AMI AF: 0.0780

Gnomad AMR AF: 0.179

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.314

Gnomad SAS AF: 0.246

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.249

GnomAD4 exome AF: 0.198 AC: 6845 AN: 34566 Hom.: 822 Cov.: 0 AF XY: 0.198 AC XY: 3546 AN XY: 17906

African (AFR) AF: 0.226 AC: 246 AN: 1088

American (AMR) AF: 0.148 AC: 450 AN: 3036

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 107 AN: 664

East Asian (EAS) AF: 0.279 AC: 497 AN: 1782

South Asian (SAS) AF: 0.202 AC: 823 AN: 4082

European-Finnish (FIN) AF: 0.266 AC: 290 AN: 1092

Middle Eastern (MID) AF: 0.167 AC: 22 AN: 132

European-Non Finnish (NFE) AF: 0.193 AC: 4031 AN: 20850

Other (OTH) AF: 0.206 AC: 379 AN: 1840

GnomAD4 genome AF: 0.245 AC: 37182 AN: 152018 Hom.: 4677 Cov.: 32 AF XY: 0.245 AC XY: 18223 AN XY: 74294

African (AFR) AF: 0.293 AC: 12161 AN: 41454

American (AMR) AF: 0.178 AC: 2726 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 780 AN: 3460

East Asian (EAS) AF: 0.314 AC: 1620 AN: 5152

South Asian (SAS) AF: 0.244 AC: 1175 AN: 4812

European-Finnish (FIN) AF: 0.295 AC: 3126 AN: 10582

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14930 AN: 67962

Other (OTH) AF: 0.249 AC: 527 AN: 2114

Alfa AF: 0.120 Hom.: 182

Bravo AF: 0.238

Asia WGS AF: 0.265 AC: 922 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.46
DANN	Benign	0.28
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

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: rs94499; hg19: chr11-134023728;