1-169982837-A-C

Position:

• chr1-169982837-A-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The ENST00000361580.7(KIFAP3):​c.1537T>G​(p.Ser513Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000426 in 1,601,134 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: KIFAP3 ENST00000361580.7 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.58

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0064940155).
• BP6: Variant 1-169982837-A-C is Benign according to our data. Variant chr1-169982837-A-C is described in ClinVar as [Benign]. Clinvar id is 3048020.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIFAP3	NM_014970.4	c.1537T>G	p.Ser513Ala	missense_variant	14/20	ENST00000361580.7	NP_055785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIFAP3	ENST00000361580.7	c.1537T>G	p.Ser513Ala	missense_variant	14/20	1	NM_014970.4	ENSP00000354560.2
KIFAP3	ENST00000367767.5	c.1405T>G	p.Ser469Ala	missense_variant	13/19	1		ENSP00000356741.1
KIFAP3	ENST00000367765.5	c.1417T>G	p.Ser473Ala	missense_variant	14/20	2		ENSP00000356739.1
KIFAP3	ENST00000538366.5	c.1303T>G	p.Ser435Ala	missense_variant	15/21	2		ENSP00000444622.1

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 326 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00760

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000554 AC: 135 AN: 243548 Hom.: 0 AF XY: 0.000424 AC XY: 56 AN XY: 132084

Gnomad AFR exome AF: 0.00780

Gnomad AMR exome AF: 0.000304

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000668

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000246 AC: 357 AN: 1448962 Hom.: 1 Cov.: 28 AF XY: 0.000207 AC XY: 149 AN XY: 720796

Gnomad4 AFR exome AF: 0.00945

Gnomad4 AMR exome AF: 0.000319

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000475

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000362

Gnomad4 OTH exome AF: 0.000401

GnomAD4 genome AF: 0.00214 AC: 325 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.00200 AC XY: 149 AN XY: 74400

Gnomad4 AFR AF: 0.00755

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000499 Hom.: 0

Bravo AF: 0.00239

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000577 AC: 70

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Dec 23, 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	Benign	0.088
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;.;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.0065	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;.;L;.
MutationTaster	Benign	0.83	D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.74	N;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.32	T;T;T;T
Sift4G	Benign	0.74	T;T;T;T
Polyphen		0.019	.;.;B;.
Vest4		0.29
MVP		0.44
MPC		0.28
ClinPred		0.019	T
GERP RS		5.5
Varity_R		0.067
gMVP		0.083

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: rs12075833; hg19: chr1-169951978;