16-57761044-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001130100.2(KIFC3):c.2000C>T(p.Thr667Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,607,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: KIFC3 NM_001130100.2 missense, splice_region
• Scores: Splicing: ADA: 0.08680
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.95

Genes affected

KIFC3 (HGNC:6326): (kinesin family member C3) This gene encodes a member of the kinesin-14 family of microtubule motors. Members of this family play a role in the formation, maintenance and remodeling of the bipolar mitotic spindle. The protein encoded by this gene has cytoplasmic functions in the interphase cells. It may also be involved in the final stages of cytokinesis. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25090098).
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIFC3	NM_001130100.2	c.2000C>T	p.Thr667Met	missense_variant, splice_region_variant	15/20	ENST00000445690.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIFC3	ENST00000445690.7	c.2000C>T	p.Thr667Met	missense_variant, splice_region_variant	15/20	1	NM_001130100.2	A1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000117 AC: 29 AN: 247074 Hom.: 0 AF XY: 0.0000970 AC XY: 13 AN XY: 133992

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000179

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000207 AC: 302 AN: 1455692 Hom.: 0 Cov.: 35 AF XY: 0.000209 AC XY: 151 AN XY: 723422

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000673

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000244

Gnomad4 OTH exome AF: 0.000249

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 22, 2023

The c.2000C>T (p.T667M) alteration is located in exon 15 (coding exon 14) of the KIFC3 gene. This alteration results from a C to T substitution at nucleotide position 2000, causing the threonine (T) at amino acid position 667 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	24
Dann	Benign	0.95
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.8	N;N;N;N;N;N;N;N;N
Sift	Benign	0.035	D;T;T;D;T;D;D;D;T
Sift4G	Benign	0.15	T;T;T;T;T;T;T;T;T
Polyphen		0.31, 0.28, 0.17	.;B;.;.;.;B;B;.;.
Vest4		0.34
MVP		0.70
MPC		0.65
ClinPred		0.043	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.087
dbscSNV1_RF	Benign	0.21
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

Publications

LitVar

Other links and lift over

dbSNP: rs150459486; hg19: chr16-57794956; COSMIC: COSV65549904; COSMIC: COSV65549904;