chr1-200553438-G-C

Position:

• chr1-200553438-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014875.3(KIF14):​c.4897C>G​(p.Pro1633Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,613,436 control chromosomes in the GnomAD database, including 117,543 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (7722 hom., cov: 31)
  • Exomes 𝑓: 0.38 (109821 hom.)
• Consequence: KIF14 NM_014875.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0450

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.403029E-4).
• BP6: Variant 1-200553438-G-C is Benign according to our data. Variant chr1-200553438-G-C is described in ClinVar as [Benign]. Clinvar id is 1223272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF14	NM_014875.3	c.4897C>G	p.Pro1633Ala	missense_variant	30/30	ENST00000367350.5	NP_055690.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF14	ENST00000367350.5	c.4897C>G	p.Pro1633Ala	missense_variant	30/30	2	NM_014875.3	ENSP00000356319	P1
KIF14	ENST00000614960.4	c.4897C>G	p.Pro1633Ala	missense_variant	29/29	1		ENSP00000483069	P1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43678 AN: 151794 Hom.: 7725 Cov.: 31

Gnomad AFR AF: 0.0913

Gnomad AMI AF: 0.425

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.446

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.401

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.344

GnomAD3 exomes AF: 0.318 AC: 79911 AN: 251216 Hom.: 14164 AF XY: 0.330 AC XY: 44822 AN XY: 135760

Gnomad AFR exome AF: 0.0859

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.427

Gnomad EAS exome AF: 0.231

Gnomad SAS exome AF: 0.313

Gnomad FIN exome AF: 0.261

Gnomad NFE exome AF: 0.405

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.379 AC: 554322 AN: 1461524 Hom.: 109821 Cov.: 40 AF XY: 0.380 AC XY: 275957 AN XY: 727048

Gnomad4 AFR exome AF: 0.0762

Gnomad4 AMR exome AF: 0.199

Gnomad4 ASJ exome AF: 0.435

Gnomad4 EAS exome AF: 0.240

Gnomad4 SAS exome AF: 0.312

Gnomad4 FIN exome AF: 0.265

Gnomad4 NFE exome AF: 0.411

Gnomad4 OTH exome AF: 0.363

GnomAD4 genome AF: 0.288 AC: 43675 AN: 151912 Hom.: 7722 Cov.: 31 AF XY: 0.280 AC XY: 20795 AN XY: 74206

Gnomad4 AFR AF: 0.0912

Gnomad4 AMR AF: 0.267

Gnomad4 ASJ AF: 0.446

Gnomad4 EAS AF: 0.232

Gnomad4 SAS AF: 0.309

Gnomad4 FIN AF: 0.263

Gnomad4 NFE AF: 0.406

Gnomad4 OTH AF: 0.344

Alfa AF: 0.385 Hom.: 8895

Bravo AF: 0.280

TwinsUK AF: 0.413 AC: 1532

ALSPAC AF: 0.417 AC: 1606

ESP6500AA AF: 0.103 AC: 454

ESP6500EA AF: 0.410 AC: 3523

ExAC AF: 0.320 AC: 38810

Asia WGS AF: 0.230 AC: 802 AN: 3478

EpiCase AF: 0.416

EpiControl AF: 0.418

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Microcephaly 20, primary, autosomal recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.0
DANN	Benign	0.82
DEOGEN2	Benign	0.057	T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.41	T;.
MetaRNN	Benign	0.00064	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.1	.;N
REVEL	Benign	0.048
Sift	Benign	0.091	.;T
Sift4G	Benign	0.16	T;T
Polyphen		0.31	B;B
Vest4		0.039
MPC		0.080
ClinPred		0.0043	T
GERP RS		0.60
Varity_R		0.036
gMVP		0.12

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: rs12120084; hg19: chr1-200522566; COSMIC: COSV66261786;