chr11-134157939-G-A

Variant names:

• chr11-134157939-G-A
• rs116394634
• NM_015261.3:c.4163C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015261.3(NCAPD3):​c.4163C>T​(p.Thr1388Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 1,613,908 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (4 hom.)
• Consequence: NCAPD3 NM_015261.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0840
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038155615).
• BP6: Variant 11-134157939-G-A is Benign according to our data. Variant chr11-134157939-G-A is described in ClinVar as Benign. ClinVar VariationId is 776682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00428 (652/152294) while in subpopulation AFR AF = 0.0145 (604/41568). AF 95% confidence interval is 0.0136. There are 2 homozygotes in GnomAd4. There are 303 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 Unknown,AR gene

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.4163C>T	p.Thr1388Met	missense	Exon 31 of 35	NP_056076.1	P42695
	NCAPD3	NM_001372068.1		c.4163C>T	p.Thr1388Met	missense	Exon 31 of 35	NP_001358997.1	A0A8I5KT00
	NCAPD3	NM_001372065.1		c.4163C>T	p.Thr1388Met	missense	Exon 31 of 34	NP_001358994.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCAPD3	ENST00000534548.7	TSL:1 MANE Select	c.4163C>T	p.Thr1388Met	missense	Exon 31 of 35	ENSP00000433681.3	P42695
	NCAPD3	ENST00000525964.7	TSL:1	n.*1805C>T		non_coding_transcript_exon	Exon 32 of 36	ENSP00000431612.2	E9PKK4
	NCAPD3	ENST00000525964.7	TSL:1	n.*1805C>T		3_prime_UTR	Exon 32 of 36	ENSP00000431612.2	E9PKK4

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 651 AN: 152176 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00126 AC: 316 AN: 251124 AF XY: 0.00104

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000555 AC: 811 AN: 1461614 Hom.: 4 Cov.: 31 AF XY: 0.000509 AC XY: 370 AN XY: 727106

African (AFR) AF: 0.0138 AC: 461 AN: 33474

American (AMR) AF: 0.00168 AC: 75 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.000156 AC: 173 AN: 1111836

Other (OTH) AF: 0.00144 AC: 87 AN: 60380

GnomAD4 genome AF: 0.00428 AC: 652 AN: 152294 Hom.: 2 Cov.: 33 AF XY: 0.00407 AC XY: 303 AN XY: 74462

African (AFR) AF: 0.0145 AC: 604 AN: 41568

American (AMR) AF: 0.00209 AC: 32 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68028

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00114 Hom.: 3

Bravo AF: 0.00477

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00133 AC: 161

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	6.7
DANN	Benign	0.91
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.84	L
PhyloP100		0.084
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.058
Sift	Benign	0.091	T
Sift4G	Benign	0.15	T
Polyphen		0.032	B
Vest4		0.085
MVP		0.16
MPC		0.079
ClinPred		0.0030	T
GERP RS		-5.2
PromoterAI		0.0097	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.011
gMVP		0.34
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs116394634; hg19: chr11-134027834; COSMIC: COSV101592162; COSMIC: COSV101592162;