rs75876570

Variant names:

• chr10-92649829-T-A
• rs75876570
• NM_004523.4:c.2771-6T>A

Your query was ambiguous. Multiple possible variants found:

• chr10-92649829-T-A
• chr10-92649829-T-C

Variant summary

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

The NM_004523.4(KIF11):​c.2771-6T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,588,138 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (40 hom.)
• Consequence: KIF11 NM_004523.4 splice_region, intron
• Scores: Splicing: ADA: 0.04179
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.160
• Publications: 3 publications found

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]

KIF11 Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 10-92649829-T-A is Benign according to our data. Variant chr10-92649829-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00546 (7845/1435868) while in subpopulation MID AF = 0.0183 (104/5684). AF 95% confidence interval is 0.0154. There are 40 homozygotes in GnomAdExome4. There are 3921 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 682 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004523.4. 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
	KIF11	NM_004523.4	MANE Select	c.2771-6T>A		splice_region intron	N/A	NP_004514.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF11	ENST00000260731.5	TSL:1 MANE Select	c.2771-6T>A		splice_region intron	N/A	ENSP00000260731.3	P52732
	KIF11	ENST00000937278.1		c.2606-6T>A		splice_region intron	N/A	ENSP00000607337.1
	KIF11	ENST00000676647.1		c.2564-6T>A		splice_region intron	N/A	ENSP00000503394.1	A0A7I2V3A9

Frequencies

GnomAD3 genomes AF: 0.00448 AC: 682 AN: 152152 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00583

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00494 AC: 1219 AN: 246914 AF XY: 0.00528

Gnomad AFR exome AF: 0.000807

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000556

Gnomad NFE exome AF: 0.00657

Gnomad OTH exome AF: 0.00632

GnomAD4 exome AF: 0.00546 AC: 7845 AN: 1435868 Hom.: 40 Cov.: 28 AF XY: 0.00551 AC XY: 3921 AN XY: 711722

African (AFR) AF: 0.00112 AC: 37 AN: 32932

American (AMR) AF: 0.00450 AC: 195 AN: 43288

Ashkenazi Jewish (ASJ) AF: 0.0139 AC: 355 AN: 25586

East Asian (EAS) AF: 0.00 AC: 0 AN: 39306

South Asian (SAS) AF: 0.00448 AC: 373 AN: 83194

European-Finnish (FIN) AF: 0.000888 AC: 47 AN: 52926

Middle Eastern (MID) AF: 0.0183 AC: 104 AN: 5684

European-Non Finnish (NFE) AF: 0.00578 AC: 6322 AN: 1093672

Other (OTH) AF: 0.00695 AC: 412 AN: 59280

GnomAD4 genome AF: 0.00448 AC: 682 AN: 152270 Hom.: 3 Cov.: 32 AF XY: 0.00461 AC XY: 343 AN XY: 74444

African (AFR) AF: 0.00128 AC: 53 AN: 41534

American (AMR) AF: 0.00797 AC: 122 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3472

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

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4820

European-Finnish (FIN) AF: 0.000661 AC: 7 AN: 10598

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00584 AC: 397 AN: 68034

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00701 Hom.: 5

Bravo AF: 0.00451

Asia WGS AF: 0.00347 AC: 12 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.7
DANN	Benign	0.46
PhyloP100		0.16
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.042
dbscSNV1_RF	Benign	0.42
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: rs75876570; hg19: chr10-94409586; COSMIC: COSV53270285;