rs376405554

Variant names:

• chrX-70405915-T-A
• rs376405554
• NM_012310.5:c.2976+10T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_012310.5(KIF4A):​c.2976+10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000884 in 1,187,347 control chromosomes in the GnomAD database, including 2 homozygotes. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00044 (2 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000052 (0 hom. 18 hem.)
• Consequence: KIF4A NM_012310.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.677
• Publications: 0 publications found

Genes affected

KIF4A (HGNC:13339): (kinesin family member 4A) This gene encodes a member of the kinesin 4 subfamily of kinesin related proteins. The encoded protein is an ATP dependent microtubule-based motor protein that is involved in the intracellular transport of membranous organelles. This protein also associates with condensed chromosome arms and may be involved in maintaining chromosome integrity during mitosis. This protein may also be involved in the organization of the central spindle prior to cytokinesis. A pseudogene of this gene is found on chromosome X.[provided by RefSeq, Mar 2010]

KIF4A Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 100

  Inheritance: Unknown, XL Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant X-70405915-T-A is Benign according to our data. Variant chrX-70405915-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 435644.
• BS2: High Homozygotes in GnomAd4 at 2 Unknown,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF4A	NM_012310.5	c.2976+10T>A		intron_variant	Intron 26 of 30	ENST00000374403.4	NP_036442.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF4A	ENST00000374403.4	c.2976+10T>A		intron_variant	Intron 26 of 30	1	NM_012310.5	ENSP00000363524.3

Frequencies

GnomAD3 genomes AF: 0.000432 AC: 48 AN: 110994 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00227

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000378

Gnomad OTH AF: 0.00270

GnomAD2 exomes AF: 0.0000549 AC: 10 AN: 182276 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000580

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000445

GnomAD4 exome AF: 0.0000520 AC: 56 AN: 1076298 Hom.: 0 Cov.: 27 AF XY: 0.0000525 AC XY: 18 AN XY: 342798

African (AFR) AF: 0.00 AC: 0 AN: 26004

American (AMR) AF: 0.00 AC: 0 AN: 35182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19251

East Asian (EAS) AF: 0.000465 AC: 14 AN: 30110

South Asian (SAS) AF: 0.00 AC: 0 AN: 53542

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4078

European-Non Finnish (NFE) AF: 0.00000365 AC: 3 AN: 822225

Other (OTH) AF: 0.000859 AC: 39 AN: 45396

GnomAD4 genome AF: 0.000441 AC: 49 AN: 111049 Hom.: 2 Cov.: 23 AF XY: 0.0000300 AC XY: 1 AN XY: 33295

African (AFR) AF: 0.00 AC: 0 AN: 30607

American (AMR) AF: 0.00327 AC: 34 AN: 10390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.00227 AC: 8 AN: 3519

South Asian (SAS) AF: 0.00 AC: 0 AN: 2565

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5959

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000378 AC: 2 AN: 52972

Other (OTH) AF: 0.00333 AC: 5 AN: 1500

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.000128

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Mar 03, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KIF4A-related disorder Benign:1

May 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.61
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs376405554; hg19: chrX-69625765;