6-168038646-C-G

Variant names:

• chr6-168038646-C-G
• rs773720591
• NM_030615.4:c.411C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030615.4(KIF25):​c.411C>G​(p.Asp137Glu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KIF25 NM_030615.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.174

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08519524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF25	NM_030615.4	c.411C>G	p.Asp137Glu	missense_variant	Exon 9 of 13	ENST00000643607.3	NP_085118.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF25	ENST00000643607.3	c.411C>G	p.Asp137Glu	missense_variant	Exon 9 of 13		NM_030615.4	ENSP00000496229.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251474 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135922

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.411C>G (p.D137E) alteration is located in exon 5 (coding exon 4) of the KIF25 gene. This alteration results from a C to G substitution at nucleotide position 411, causing the aspartic acid (D) at amino acid position 137 to be replaced by a glutamic acid (E). 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	0.20
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	11
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;T;T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.072	N
LIST_S2	Benign	0.60	.;.;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.085	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.91	L;L;L;L
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.4	.;N;N;D
REVEL	Benign	0.19
Sift	Benign	0.082	.;T;T;T
Sift4G	Benign	0.14	.;T;T;T
Polyphen		0.38	B;B;B;P
Vest4		0.19, 0.19, 0.20
MutPred		0.34		Gain of ubiquitination at K136 (P = 0.1106);Gain of ubiquitination at K136 (P = 0.1106);Gain of ubiquitination at K136 (P = 0.1106);Gain of ubiquitination at K136 (P = 0.1106);
MVP		0.71
MPC		0.29
ClinPred		0.46	T
GERP RS		2.0
Varity_R		0.14
gMVP		0.13

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: rs773720591; hg19: chr6-168439326;