12-39294187-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.*237A>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 0.25 in 411,246 control chromosomes in the GnomAD database, including 16,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (8435 hom., cov: 32)
  • Exomes 𝑓: 0.22 (7901 hom.)
• Consequence: KIF21A NM_001173464.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.49

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=-0.82).
• BP6: Variant 12-39294187-T-C is Benign according to our data. Variant chr12-39294187-T-C is described in ClinVar as [Benign]. Clinvar id is 308542.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF21A	NM_001173464.2	c.*237A>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.*237A>G		3_prime_UTR_variant	38/38	1	NM_001173464.2	A1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 45017 AN: 151924 Hom.: 8396 Cov.: 32

Gnomad AFR AF: 0.528

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.157

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.277

GnomAD4 exome AF: 0.223 AC: 57680 AN: 259204 Hom.: 7901 Cov.: 2 AF XY: 0.232 AC XY: 31692 AN XY: 136876

Gnomad4 AFR exome AF: 0.518

Gnomad4 AMR exome AF: 0.210

Gnomad4 ASJ exome AF: 0.141

Gnomad4 EAS exome AF: 0.345

Gnomad4 SAS exome AF: 0.383

Gnomad4 FIN exome AF: 0.159

Gnomad4 NFE exome AF: 0.179

Gnomad4 OTH exome AF: 0.218

GnomAD4 genome AF: 0.297 AC: 45109 AN: 152042 Hom.: 8435 Cov.: 32 AF XY: 0.298 AC XY: 22137 AN XY: 74330

Gnomad4 AFR AF: 0.529

Gnomad4 AMR AF: 0.235

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.379

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.157

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.282

Alfa AF: 0.208 Hom.: 3751

Bravo AF: 0.308

Asia WGS AF: 0.393 AC: 1361 AN: 3478

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	-0.82
Cadd	Benign	1.3
Dann	Benign	0.73

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs11171675; hg19: chr12-39687989;