5-155014626-G-C

Position:

• chr5-155014626-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001099293.3(KIF4B):​c.767G>C​(p.Arg256Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KIF4B NM_001099293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.26

Genes affected

KIF4B (HGNC:6322): (kinesin family member 4B) This gene is an intronless retrocopy of kinesin family member 4A. The protein encoded by this gene is a microtubule-based motor protein that plays vital roles in anaphase spindle dynamics and cytokinesis. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF4B	NM_001099293.3	c.767G>C	p.Arg256Pro	missense_variant	1/1	ENST00000435029.6	NP_001092763.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF4B	ENST00000435029.6	c.767G>C	p.Arg256Pro	missense_variant	1/1		NM_001099293.3	ENSP00000387875	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.767G>C (p.R256P) alteration is located in exon 1 (coding exon 1) of the KIF4B gene. This alteration results from a G to C substitution at nucleotide position 767, causing the arginine (R) at amino acid position 256 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.0066	T
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.092	D
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.85		Gain of ubiquitination at K258 (P = 0.0373);
MVP		0.58
MPC		0.56
ClinPred		1.0	D
GERP RS		-0.20
Varity_R		0.82
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs753391654; hg19: chr5-154394186;