rs77828651

Variant names:

• chr1-200617637-C-T
• rs77828651
• NM_014875.3:c.1087G>A
• KIF14 p.Val363Ile

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014875.3(KIF14):​c.1087G>A​(p.Val363Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,611,654 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (17 hom.)
• Consequence: KIF14 NM_014875.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.31
• Publications: 5 publications found

Genes affected

KIF14 (HGNC:19181): (kinesin family member 14) This gene encodes a member of the kinesin-3 superfamily of microtubule motor proteins. These proteins are involved in numerous processes including vesicle transport, chromosome segregation, mitotic spindle formation, and cytokinesis. In human HeLa-S3 and 293T cells, this protein is localized to the cytoplasm during interphase, to the spindle poles and spindle microtubules during mitosis, and to the midbody during cytokinesis. An internal motor domain displays microtubule-dependent ATPase activity, consistent with its function as a microtubule motor protein. Knockdown of this gene results in failed cytokinesis with endoreplication, which results in multinucleated cells. This gene has been identified as a likely oncogene in breast, lung and ovarian cancers, as well as retinoblastomas and gliomas. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]

KIF14 Gene-Disease associations (from GenCC):

• autosomal recessive primary microcephaly

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• microcephaly 20, primary, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016474038).
• BP6: Variant 1-200617637-C-T is Benign according to our data. Variant chr1-200617637-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 435619.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00251 (383/152360) while in subpopulation SAS AF = 0.00372 (18/4834). AF 95% confidence interval is 0.00319. There are 1 homozygotes in GnomAd4. There are 192 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014875.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF14	NM_014875.3	MANE Select	c.1087G>A	p.Val363Ile	missense	Exon 2 of 30	NP_055690.1	Q15058
	KIF14	NM_001305792.1		c.-299G>A		5_prime_UTR	Exon 1 of 28	NP_001292721.1	Q15058

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF14	ENST00000367350.5	TSL:2 MANE Select	c.1087G>A	p.Val363Ile	missense	Exon 2 of 30	ENSP00000356319.4	Q15058
	KIF14	ENST00000614960.4	TSL:1	c.1087G>A	p.Val363Ile	missense	Exon 1 of 29	ENSP00000483069.1	Q15058
	KIF14	ENST00000928797.1		c.1087G>A	p.Val363Ile	missense	Exon 2 of 31	ENSP00000598856.1

Frequencies

GnomAD3 genomes AF: 0.00252 AC: 383 AN: 152242 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00356

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00295 AC: 738 AN: 250560 AF XY: 0.00318

Gnomad AFR exome AF: 0.000801

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00644

Gnomad NFE exome AF: 0.00361

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00375 AC: 5468 AN: 1459294 Hom.: 17 Cov.: 32 AF XY: 0.00373 AC XY: 2709 AN XY: 725634

African (AFR) AF: 0.000841 AC: 28 AN: 33304

American (AMR) AF: 0.00182 AC: 81 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.000460 AC: 12 AN: 26076

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39642

South Asian (SAS) AF: 0.00384 AC: 331 AN: 86120

European-Finnish (FIN) AF: 0.00594 AC: 317 AN: 53396

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5760

European-Non Finnish (NFE) AF: 0.00408 AC: 4526 AN: 1110292

Other (OTH) AF: 0.00270 AC: 163 AN: 60262

GnomAD4 genome AF: 0.00251 AC: 383 AN: 152360 Hom.: 1 Cov.: 33 AF XY: 0.00258 AC XY: 192 AN XY: 74508

African (AFR) AF: 0.000673 AC: 28 AN: 41586

American (AMR) AF: 0.00235 AC: 36 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00372 AC: 18 AN: 4834

European-Finnish (FIN) AF: 0.00490 AC: 52 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00356 AC: 242 AN: 68038

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00331 Hom.: 2

Bravo AF: 0.00231

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	KIF14-related disorder (1)
-	-	1	Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome;C4693572:Microcephaly 20, primary, autosomal recessive (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	-0.025	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.24
Sift	Benign	0.19	T
Sift4G	Benign	0.15	T
Varity_R		0.17
gMVP		0.30
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs77828651;

hg19: chr1-200586765;