rs981349334

Variant names:

• chr1-200565669-C-A
• rs981349334
• NM_014875.3:c.3662G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_014875.3(KIF14):​c.3662G>T​(p.Gly1221Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000709 in 1,410,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KIF14 NM_014875.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.45
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• microcephaly 20, primary, autosomal recessive

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-200565669-C-A is Pathogenic according to our data. Variant chr1-200565669-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 503569.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF14	NM_014875.3	c.3662G>T	p.Gly1221Val	missense_variant, splice_region_variant	Exon 24 of 30	ENST00000367350.5	NP_055690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF14	ENST00000367350.5	c.3662G>T	p.Gly1221Val	missense_variant, splice_region_variant	Exon 24 of 30	2	NM_014875.3	ENSP00000356319.4
KIF14	ENST00000614960.4	c.3662G>T	p.Gly1221Val	missense_variant, splice_region_variant	Exon 23 of 29	1		ENSP00000483069.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 213554 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410668 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 700886

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30894

American (AMR) AF: 0.00 AC: 0 AN: 31754

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39182

South Asian (SAS) AF: 0.00 AC: 0 AN: 78432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52444

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4172

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091910

Other (OTH) AF: 0.00 AC: 0 AN: 58014

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly 20, primary, autosomal recessive Pathogenic:1

Mar 28, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Joubert syndrome and related disorders Pathogenic:1

May 28, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KIF14 c.3662G>T (p.Gly1221Val) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function all suggest that this variant is likely to be disruptive. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 3' acceptor site. One predict the variant no significant impact on splicing. Three predict the variant abolishes a cryptic 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Moawia_2017). The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.3662G>T has been observed as compound heterozygous genotype in an individual affected with clinical features of Joubert Syndrome And Related Disorders (Moawia_2017). The following publication have been ascertained in the context of this evaluation (PMID: 28892560). ClinVar contains an entry for this variant (Variation ID: 503569). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.71	T;.
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.9	M;M
PhyloP100		4.4
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-5.0	.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.010	.;D
Sift4G	Uncertain	0.016	D;D
Polyphen		1.0	D;D
Vest4		0.68
MutPred		0.15		Loss of glycosylation at S1220 (P = 0.0213);Loss of glycosylation at S1220 (P = 0.0213);
MVP		0.91
MPC		0.35
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.69
gMVP		0.51
Mutation Taster		=16/84	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.74		Position offset: 0

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

Other links and lift over

dbSNP: rs981349334; hg19: chr1-200534797;