12-39294006-T-C

Position:

• chr12-39294006-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001173464.2(KIF21A):​c.*418A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0578 in 169,238 control chromosomes in the GnomAD database, including 1,038 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.064 (1034 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (4 hom.)
• Consequence: KIF21A NM_001173464.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.385

Genes affected

KIF21A (HGNC:19349): (kinesin family member 21A) This gene encodes a member of the KIF4 subfamily of kinesin-like motor proteins. The encoded protein is characterized by an N-terminal motor domain a coiled-coil stalk domain and a C-terminal WD-40 repeat domain. This protein may be involved in microtubule dependent transport. Mutations in this gene are the cause of congenital fibrosis of extraocular muscles-1. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-39294006-T-C is Benign according to our data. Variant chr12-39294006-T-C is described in ClinVar as [Benign]. Clinvar id is 308540.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF21A	NM_001173464.2	c.*418A>G		3_prime_UTR_variant	38/38	ENST00000361418.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF21A	ENST00000361418.10	c.*418A>G		3_prime_UTR_variant	38/38	1	NM_001173464.2	A1

Frequencies

GnomAD3 genomes AF: 0.0637 AC: 9699 AN: 152148 Hom.: 1031 Cov.: 33

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.0444

GnomAD4 exome AF: 0.00324 AC: 55 AN: 16972 Hom.: 4 Cov.: 0 AF XY: 0.00294 AC XY: 26 AN XY: 8836

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000188

Gnomad4 OTH exome AF: 0.0124

GnomAD4 genome AF: 0.0638 AC: 9719 AN: 152266 Hom.: 1034 Cov.: 33 AF XY: 0.0617 AC XY: 4595 AN XY: 74470

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.0225

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0524 Hom.: 86

Bravo AF: 0.0725

Asia WGS AF: 0.0110 AC: 39 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital fibrosis of extraocular muscles type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.7
DANN	Benign	0.81

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs77242017; hg19: chr12-39687808;