chr1-170016518-C-T

Position:

• chr1-170016518-C-T

Variant summary

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

The NM_014970.4(KIFAP3):​c.1127G>A​(p.Gly376Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 5.73

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIFAP3	NM_014970.4	c.1127G>A	p.Gly376Glu	missense_variant	10/20	ENST00000361580.7	NP_055785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIFAP3	ENST00000361580.7	c.1127G>A	p.Gly376Glu	missense_variant	10/20	1	NM_014970.4	ENSP00000354560.2
KIFAP3	ENST00000367767.5	c.995G>A	p.Gly332Glu	missense_variant	9/19	1		ENSP00000356741.1
KIFAP3	ENST00000367765.5	c.1007G>A	p.Gly336Glu	missense_variant	10/20	2		ENSP00000356739.1
KIFAP3	ENST00000538366.5	c.893G>A	p.Gly298Glu	missense_variant	11/21	2		ENSP00000444622.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Sep 15, 2021

The c.1127G>A (p.G376E) alteration is located in exon 10 (coding exon 10) of the KIFAP3 gene. This alteration results from a G to A substitution at nucleotide position 1127, causing the glycine (G) at amino acid position 376 to be replaced by a glutamic acid (E). 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	Uncertain	0.55
BayesDel_addAF	Benign	-0.081	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.79
DEOGEN2	Benign	0.050	.;.;T;.
Eigen	Benign	-0.095
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.50	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	.;.;N;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	1.1	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.75	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	.;.;B;.
Vest4		0.59
MutPred		0.56		.;.;Loss of loop (P = 0.0288);.;
MVP		0.50
MPC		0.43
ClinPred		0.66	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.45

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: chr1-169985659;