rs75449932

Variant names:

• chr1-200565523-T-G
• rs75449932
• NM_014875.3:c.3808A>C

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.3808A>C​(p.Ser1270Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,610,398 control chromosomes in the GnomAD database, including 57 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (56 hom.)
• Consequence: KIF14 NM_014875.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.30
• Publications: 8 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: Orphanet, Illumina
• lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=0.003931284).
• BP6: Variant 1-200565523-T-G is Benign according to our data. Variant chr1-200565523-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0049 (746/152324) while in subpopulation NFE AF = 0.00756 (514/68020). AF 95% confidence interval is 0.00702. There are 1 homozygotes in GnomAd4. There are 366 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 56 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.3808A>C	p.Ser1270Arg	missense	Exon 24 of 30	NP_055690.1	Q15058
	KIF14	NM_001305792.1		c.2335A>C	p.Ser779Arg	missense	Exon 22 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.3808A>C	p.Ser1270Arg	missense	Exon 24 of 30	ENSP00000356319.4	Q15058
	KIF14	ENST00000614960.4	TSL:1	c.3808A>C	p.Ser1270Arg	missense	Exon 23 of 29	ENSP00000483069.1	Q15058
	KIF14	ENST00000928797.1		c.3925A>C	p.Ser1309Arg	missense	Exon 25 of 31	ENSP00000598856.1

Frequencies

GnomAD3 genomes AF: 0.00490 AC: 746 AN: 152206 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00756

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00564 AC: 1397 AN: 247832 AF XY: 0.00582

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000803

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.00906

Gnomad OTH exome AF: 0.00396

GnomAD4 exome AF: 0.00660 AC: 9626 AN: 1458074 Hom.: 56 Cov.: 31 AF XY: 0.00633 AC XY: 4594 AN XY: 725184

African (AFR) AF: 0.000992 AC: 33 AN: 33254

American (AMR) AF: 0.00120 AC: 53 AN: 44046

Ashkenazi Jewish (ASJ) AF: 0.000844 AC: 22 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39598

South Asian (SAS) AF: 0.000635 AC: 54 AN: 85050

European-Finnish (FIN) AF: 0.0123 AC: 657 AN: 53390

Middle Eastern (MID) AF: 0.000738 AC: 4 AN: 5418

European-Non Finnish (NFE) AF: 0.00769 AC: 8542 AN: 1111032

Other (OTH) AF: 0.00433 AC: 261 AN: 60232

GnomAD4 genome AF: 0.00490 AC: 746 AN: 152324 Hom.: 1 Cov.: 32 AF XY: 0.00491 AC XY: 366 AN XY: 74490

African (AFR) AF: 0.00113 AC: 47 AN: 41576

American (AMR) AF: 0.00261 AC: 40 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

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

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.0112 AC: 119 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00756 AC: 514 AN: 68020

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00703 Hom.: 28

Bravo AF: 0.00424

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00559 AC: 48

ExAC AF: 0.00632 AC: 767

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.11
Sift	Benign	0.033	D
Sift4G	Benign	0.074	T
Polyphen		0.11	B
Vest4		0.26
MutPred		0.29		Loss of ubiquitination at K1273 (P = 0.0391)
MVP		0.59
MPC		0.12
ClinPred		0.0083	T
GERP RS		4.4
Varity_R		0.18
gMVP		0.24
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs75449932; hg19: chr1-200534651; COSMIC: COSV100951028;