1-169954083-A-G

Position:

• chr1-169954083-A-G

Variant summary

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

The NM_014970.4(KIFAP3):​c.2201T>C​(p.Ile734Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIFAP3 NM_014970.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.63

Genes affected

KIFAP3 (HGNC:17060): (kinesin associated protein 3) The small G protein GDP dissociation stimulator (smg GDS) is a regulator protein having two activities on a group of small G proteins including the Rho and Rap1 family members and Ki-Ras; one is to stimulate their GDP/GTP exchange reactions, and the other is to inhibit their interactions with membranes. The protein encoded by this gene contains 9 'Armadillo' repeats and interacts with the smg GDS protein through these repeats. This protein, which is highly concentrated around the endoplasmic reticulum, is phosphorylated by v-src, and this phosphorylation reduces the affinity of the protein for smg GDS. It is thought that this protein serves as a linker between human chromosome-associated polypeptide (HCAP) and KIF3A/B, a kinesin superfamily protein in the nucleus, and that it plays a role in the interaction of chromosomes with an ATPase motor protein. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

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=0.21265346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIFAP3	NM_014970.4	c.2201T>C	p.Ile734Thr	missense_variant	19/20	ENST00000361580.7	NP_055785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIFAP3	ENST00000361580.7	c.2201T>C	p.Ile734Thr	missense_variant	19/20	1	NM_014970.4	ENSP00000354560.2
KIFAP3	ENST00000367767.5	c.2069T>C	p.Ile690Thr	missense_variant	18/19	1		ENSP00000356741.1
KIFAP3	ENST00000367765.5	c.2081T>C	p.Ile694Thr	missense_variant	19/20	2		ENSP00000356739.1
KIFAP3	ENST00000538366.5	c.1967T>C	p.Ile656Thr	missense_variant	20/21	2		ENSP00000444622.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2023

The c.2201T>C (p.I734T) alteration is located in exon 19 (coding exon 19) of the KIFAP3 gene. This alteration results from a T to C substitution at nucleotide position 2201, causing the isoleucine (I) at amino acid position 734 to be replaced by a threonine (T). 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	0.21
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	.;.;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.0084
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	.;.;N;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.91	N;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.065	T;T;T;T
Sift4G	Benign	0.62	T;T;T;T
Polyphen		0.0020	.;.;B;.
Vest4		0.36
MVP		0.59
MPC		0.41
ClinPred		0.64	D
GERP RS		4.2
Varity_R		0.075
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-169923224;