6-168040135-A-G

Position:

• chr6-168040135-A-G

Variant summary

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

The NM_030615.4(KIF25):​c.565A>G​(p.Thr189Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF25 NM_030615.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.72

Genes affected

KIF25 (HGNC:6390): (kinesin family member 25) The protein encoded by this gene is a member of the kinesin-like protein family. Protein family members are microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division. However, the particular function of this gene product has not yet been determined. Two alternatively spliced transcript variants which encode products have been described. Other splice variants have been found that lack exon 2 and the initiation codon for translation. [provided by RefSeq, Jul 2008]

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, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF25	NM_030615.4	c.565A>G	p.Thr189Ala	missense_variant	10/13	ENST00000643607.3	NP_085118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF25	ENST00000643607.3	c.565A>G	p.Thr189Ala	missense_variant	10/13		NM_030615.4	ENSP00000496229	P1
KIF25	ENST00000443060.6	c.565A>G	p.Thr189Ala	missense_variant	7/10	5		ENSP00000388878	P1
KIF25	ENST00000644536.1	n.827A>G		non_coding_transcript_exon_variant	6/9
KIF25	ENST00000645382.1	n.799A>G		non_coding_transcript_exon_variant	6/8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

May 16, 2022

The c.565A>G (p.T189A) alteration is located in exon 6 (coding exon 5) of the KIF25 gene. This alteration results from a A to G substitution at nucleotide position 565, causing the threonine (T) at amino acid position 189 to be replaced by an alanine (A). 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	0.10
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.63	D;D;D;.
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.81	.;.;T;T
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.4	M;M;M;M
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-4.7	.;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0060	.;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.87, 0.87, 0.76
MutPred		0.93		Gain of ubiquitination at K186 (P = 0.0661);Gain of ubiquitination at K186 (P = 0.0661);Gain of ubiquitination at K186 (P = 0.0661);Gain of ubiquitination at K186 (P = 0.0661);
MVP		0.72
MPC		0.49
ClinPred		0.99	D
GERP RS		2.9
Varity_R		0.78
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-168440815;