chr1-170034440-T-C

Position:

• chr1-170034440-T-C

Variant summary

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

The ENST00000361580.7(KIFAP3):​c.674A>G​(p.Asn225Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 ENST00000361580.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.68

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=0.22438374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIFAP3	NM_014970.4	c.674A>G	p.Asn225Ser	missense_variant	7/20	ENST00000361580.7	NP_055785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIFAP3	ENST00000361580.7	c.674A>G	p.Asn225Ser	missense_variant	7/20	1	NM_014970.4	ENSP00000354560.2
KIFAP3	ENST00000367767.5	c.542A>G	p.Asn181Ser	missense_variant	6/19	1		ENSP00000356741.1
KIFAP3	ENST00000367765.5	c.554A>G	p.Asn185Ser	missense_variant	7/20	2		ENSP00000356739.1
KIFAP3	ENST00000538366.5	c.440A>G	p.Asn147Ser	missense_variant	8/21	2		ENSP00000444622.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

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

Jun 05, 2024

The c.674A>G (p.N225S) alteration is located in exon 7 (coding exon 7) of the KIFAP3 gene. This alteration results from a A to G substitution at nucleotide position 674, causing the asparagine (N) at amino acid position 225 to be replaced by a serine (S). 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	0.070
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	.;.;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	0.020
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.42	.;.;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.43	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.48	T;T;T;T
Sift4G	Benign	0.49	T;T;T;T
Polyphen		0.0010	.;.;B;.
Vest4		0.17
MutPred		0.81		.;.;Gain of catalytic residue at N225 (P = 0.1248);.;
MVP		0.40
MPC		0.26
ClinPred		0.80	D
GERP RS		5.4
Varity_R		0.061
gMVP		0.10

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: chr1-170003581;