12-39293952-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.*472A>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 0.294 in 156,030 control chromosomes in the GnomAD database, including 8,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (8439 hom., cov: 32)
  • Exomes 𝑓: 0.17 (95 hom.)
• Consequence: KIF21A NM_001173464.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.119

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=-0.59).
• BP6: Variant 12-39293952-T-C is Benign according to our data. Variant chr12-39293952-T-C is described in ClinVar as [Benign]. Clinvar id is 308537.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF21A	NM_001173464.2	c.*472A>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.*472A>G		3_prime_UTR_variant	38/38	1	NM_001173464.2	A1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 45021 AN: 151918 Hom.: 8400 Cov.: 32

Gnomad AFR AF: 0.529

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.378

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.277

GnomAD4 exome AF: 0.175 AC: 697 AN: 3994 Hom.: 95 Cov.: 0 AF XY: 0.184 AC XY: 388 AN XY: 2106

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.0750

Gnomad4 EAS exome AF: 0.316

Gnomad4 SAS exome AF: 0.330

Gnomad4 FIN exome AF: 0.138

Gnomad4 NFE exome AF: 0.154

Gnomad4 OTH exome AF: 0.165

GnomAD4 genome AF: 0.297 AC: 45113 AN: 152036 Hom.: 8439 Cov.: 32 AF XY: 0.298 AC XY: 22136 AN XY: 74318

Gnomad4 AFR AF: 0.529

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.379

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.283

Alfa AF: 0.203 Hom.: 3494

Bravo AF: 0.308

Asia WGS AF: 0.393 AC: 1361 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	-0.59
Cadd	Benign	4.0
Dann	Benign	0.76

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11171674; hg19: chr12-39687754;