6-17764906-C-T

Position:

• chr6-17764906-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022113.6(KIF13A):​c.4622G>A​(p.Arg1541Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF13A NM_022113.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

Genes affected

KIF13A (HGNC:14566): (kinesin family member 13A) This gene encodes a member of the kinesin family of microtubule-based motor proteins that function in the positioning of endosomes. This family member can direct mannose-6-phosphate receptor-containing vesicles from the trans-Golgi network to the plasma membrane, and it is necessary for the steady-state distribution of late endosomes/lysosomes. It is also required for the translocation of FYVE-CENT and TTC19 from the centrosome to the midbody during cytokinesis, and it plays a role in melanosome maturation. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06053853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF13A	NM_022113.6	c.4622G>A	p.Arg1541Lys	missense_variant	39/39	ENST00000259711.11	NP_071396.4
KIF13A	NM_001105566.3	c.4517G>A	p.Arg1506Lys	missense_variant	38/38		NP_001099036.1
KIF13A	NM_001105567.3	c.4478G>A	p.Arg1493Lys	missense_variant	37/37		NP_001099037.1
KIF13A	NM_001105568.4	c.4478G>A	p.Arg1493Lys	missense_variant	37/38		NP_001099038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF13A	ENST00000259711.11	c.4622G>A	p.Arg1541Lys	missense_variant	39/39	1	NM_022113.6	ENSP00000259711.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000809 AC: 2 AN: 247070 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134022

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

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

Jun 06, 2023

The c.4622G>A (p.R1541K) alteration is located in exon 39 (coding exon 39) of the KIF13A gene. This alteration results from a G to A substitution at nucleotide position 4622, causing the arginine (R) at amino acid position 1541 to be replaced by a lysine (K). 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	Benign	0.065
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.83
DEOGEN2	Benign	0.0094	.;T;T;.;.;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.73	T;T;T;T;T;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.061	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.14	.;.;N;.;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.42	N;N;N;N;N;.
REVEL	Benign	0.059
Sift	Benign	0.44	T;T;T;T;T;.
Sift4G	Benign	1.0	T;T;T;T;T;.
Polyphen		0.0	B;.;B;B;B;.
Vest4		0.063
MutPred		0.38		.;.;Gain of ubiquitination at R1541 (P = 0.006);.;.;.;
MVP		0.26
MPC		0.24
ClinPred		0.023	T
GERP RS		2.8
Varity_R		0.035
gMVP		0.36

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: rs779280594; hg19: chr6-17765137;