chr1-169984674-A-C

Position:

• chr1-169984674-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000361580.7(KIFAP3):​c.1301T>G​(p.Phe434Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00201 in 1,600,084 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: KIFAP3 ENST00000361580.7 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 5.49

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009478658).
• BP6: Variant 1-169984674-A-C is Benign according to our data. Variant chr1-169984674-A-C is described in ClinVar as [Benign]. Clinvar id is 3049322.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIFAP3	NM_014970.4	c.1301T>G	p.Phe434Cys	missense_variant	12/20	ENST00000361580.7	NP_055785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIFAP3	ENST00000361580.7	c.1301T>G	p.Phe434Cys	missense_variant	12/20	1	NM_014970.4	ENSP00000354560.2
KIFAP3	ENST00000367767.5	c.1169T>G	p.Phe390Cys	missense_variant	11/19	1		ENSP00000356741.1
KIFAP3	ENST00000367765.5	c.1181T>G	p.Phe394Cys	missense_variant	12/20	2		ENSP00000356739.1
KIFAP3	ENST00000538366.5	c.1067T>G	p.Phe356Cys	missense_variant	13/21	2		ENSP00000444622.1

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 151860 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00896

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00236

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00159 AC: 393 AN: 247478 Hom.: 1 AF XY: 0.00165 AC XY: 221 AN XY: 133754

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.000974

Gnomad ASJ exome AF: 0.00777

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000168

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.00232

GnomAD4 exome AF: 0.00204 AC: 2947 AN: 1448106 Hom.: 4 Cov.: 26 AF XY: 0.00194 AC XY: 1399 AN XY: 720862

Gnomad4 AFR exome AF: 0.000543

Gnomad4 AMR exome AF: 0.00109

Gnomad4 ASJ exome AF: 0.00731

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000141

Gnomad4 FIN exome AF: 0.000263

Gnomad4 NFE exome AF: 0.00229

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00175 AC: 266 AN: 151978 Hom.: 0 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74310

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00171

Gnomad4 ASJ AF: 0.00896

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00236

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00241 Hom.: 0

Bravo AF: 0.00186

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

KIFAP3-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	.;.;T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.0095	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.2	N;N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.61
MVP		0.66
MPC		1.2
ClinPred		0.057	T
GERP RS		5.5
Varity_R		0.35
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

LitVar

Other links and lift over

dbSNP: rs116755924; hg19: chr1-169953815; COSMIC: COSV100846882;