10-68989028-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_015634.4(KIFBP):c.196G>A(p.Gly66Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,613,698 control chromosomes in the GnomAD database, including 172,227 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13505 hom., cov: 34)
  • Exomes 𝑓: 0.46 (158722 hom.)
• Consequence: KIFBP NM_015634.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.335

Genes affected

KIFBP (HGNC:23419): (kinesin family binding protein) This gene encodes a kinesin family member 1 binding protein that is characterized by two tetratrico peptide repeats. The encoded protein localizes to the mitochondria and may be involved in regulating transport of the mitochondria. Mutations in this gene are associated with Goldberg-Shprintzen megacolon syndrome. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6480684E-4).
• BP6: Variant 10-68989028-G-A is Benign according to our data. Variant chr10-68989028-G-A is described in ClinVar as [Benign]. Clinvar id is 158696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68989028-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIFBP	NM_015634.4	c.196G>A	p.Gly66Ser	missense_variant	1/7	ENST00000361983.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIFBP	ENST00000361983.7	c.196G>A	p.Gly66Ser	missense_variant	1/7	1	NM_015634.4	P1

Frequencies

GnomAD3 genomes AF: 0.415 AC: 63049 AN: 152092 Hom.: 13502 Cov.: 34

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.366

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.434

GnomAD3 exomes AF: 0.404 AC: 100114 AN: 247738 Hom.: 21164 AF XY: 0.406 AC XY: 54687 AN XY: 134566

Gnomad AFR exome AF: 0.350

Gnomad AMR exome AF: 0.293

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.372

Gnomad SAS exome AF: 0.313

Gnomad FIN exome AF: 0.395

Gnomad NFE exome AF: 0.484

Gnomad OTH exome AF: 0.401

GnomAD4 exome AF: 0.461 AC: 673191 AN: 1461488 Hom.: 158722 Cov.: 65 AF XY: 0.456 AC XY: 331844 AN XY: 727048

Gnomad4 AFR exome AF: 0.346

Gnomad4 AMR exome AF: 0.301

Gnomad4 ASJ exome AF: 0.350

Gnomad4 EAS exome AF: 0.355

Gnomad4 SAS exome AF: 0.318

Gnomad4 FIN exome AF: 0.403

Gnomad4 NFE exome AF: 0.492

Gnomad4 OTH exome AF: 0.438

GnomAD4 genome AF: 0.414 AC: 63053 AN: 152210 Hom.: 13505 Cov.: 34 AF XY: 0.407 AC XY: 30306 AN XY: 74396

Gnomad4 AFR AF: 0.347

Gnomad4 AMR AF: 0.350

Gnomad4 ASJ AF: 0.361

Gnomad4 EAS AF: 0.366

Gnomad4 SAS AF: 0.310

Gnomad4 FIN AF: 0.394

Gnomad4 NFE AF: 0.486

Gnomad4 OTH AF: 0.430

Alfa AF: 0.429 Hom.: 7720

Bravo AF: 0.411

TwinsUK AF: 0.491 AC: 1819

ALSPAC AF: 0.506 AC: 1952

ESP6500AA AF: 0.342 AC: 1507

ESP6500EA AF: 0.483 AC: 4153

ExAC AF: 0.410 AC: 49681

Asia WGS AF: 0.304 AC: 1058 AN: 3478

EpiCase AF: 0.476

EpiControl AF: 0.474

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Goldberg-Shprintzen syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	5.2
Dann	Benign	0.84
DEOGEN2	Benign	0.019	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.69	T;T;T
MetaRNN	Benign	0.00016	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L;.;.
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.030	N;.;.
REVEL	Benign	0.011
Sift	Benign	0.55	T;.;.
Sift4G	Benign	0.37	T;.;T
Polyphen		0.0	B;.;.
Vest4		0.043
MPC		0.45
ClinPred		0.00074	T
GERP RS		-0.11
Varity_R		0.037
gMVP		0.12

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: rs2255607; hg19: chr10-70748784; COSMIC: COSV62555322; COSMIC: COSV62555322;