rs34417963

chr10-92653751-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004523.4(KIF11):c.3126G>C(p.Leu1042Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,613,806 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (38 hom.)
• Consequence: KIF11 NM_004523.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.236

Genes affected

KIF11 (HGNC:6388): (kinesin family member 11) This gene encodes a motor protein that belongs to the kinesin-like protein family. Members of this protein family are known to be involved in various kinds of spindle dynamics. The function of this gene product includes chromosome positioning, centrosome separation and establishing a bipolar spindle during cell mitosis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002524376).
• BP6: Variant 10-92653751-G-C is Benign according to our data. Variant chr10-92653751-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 235554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-92653751-G-C is described in Lovd as [Benign]. Variant chr10-92653751-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1990/152226) while in subpopulation AFR AF= 0.0444 (1844/41526). AF 95% confidence interval is 0.0427. There are 49 homozygotes in gnomad4. There are 952 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1989 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF11	NM_004523.4	c.3126G>C	p.Leu1042Phe	missense_variant	22/22	ENST00000260731.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF11	ENST00000260731.5	c.3126G>C	p.Leu1042Phe	missense_variant	22/22	1	NM_004523.4	P1

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1989 AN: 152106 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.0445

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00352 AC: 884 AN: 251448 Hom.: 18 AF XY: 0.00266 AC XY: 361 AN XY: 135898

Gnomad AFR exome AF: 0.0444

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00146 AC: 2141 AN: 1461580 Hom.: 38 Cov.: 30 AF XY: 0.00131 AC XY: 951 AN XY: 727126

Gnomad4 AFR exome AF: 0.0450

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000241

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.0131 AC: 1990 AN: 152226 Hom.: 49 Cov.: 32 AF XY: 0.0128 AC XY: 952 AN XY: 74424

Gnomad4 AFR AF: 0.0444

Gnomad4 AMR AF: 0.00595

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00212 Hom.: 4

Bravo AF: 0.0139

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0395 AC: 174

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00443 AC: 538

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2022	See Variant Classification Assertion Criteria. -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.12
Dann	Uncertain	0.98
DEOGEN2	Benign	0.099	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.041
Sift	Benign	0.13	T
Sift4G	Benign	0.47	T
Polyphen		0.0010	B
Vest4		0.048
MutPred		0.12		Loss of disorder (P = 0.0861);
MVP		0.16
MPC		0.32
ClinPred		0.0029	T
GERP RS		-1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.060

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs34417963; hg19: chr10-94413508;