rs62625033

chr10-69000515-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015634.4(KIFBP):c.518T>C(p.Met173Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00786 in 1,584,916 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M173V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0061 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (66 hom.)
• Consequence: KIFBP NM_015634.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 6.47

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=0.008571029).
• BP6: Variant 10-69000515-T-C is Benign according to our data. Variant chr10-69000515-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 158697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-69000515-T-C is described in Lovd as [Benign]. Variant chr10-69000515-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00605 (922/152336) while in subpopulation NFE AF= 0.00989 (673/68026). AF 95% confidence interval is 0.00927. There are 1 homozygotes in gnomad4. There are 394 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIFBP	NM_015634.4	c.518T>C	p.Met173Thr	missense_variant	2/7	ENST00000361983.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIFBP	ENST00000361983.7	c.518T>C	p.Met173Thr	missense_variant	2/7	1	NM_015634.4	P1

Frequencies

GnomAD3 genomes AF: 0.00606 AC: 923 AN: 152218 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00989

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00650 AC: 1632 AN: 251074 Hom.: 6 AF XY: 0.00669 AC XY: 908 AN XY: 135704

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00509

Gnomad ASJ exome AF: 0.00546

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00467

Gnomad FIN exome AF: 0.00246

Gnomad NFE exome AF: 0.0100

Gnomad OTH exome AF: 0.00735

GnomAD4 exome AF: 0.00806 AC: 11542 AN: 1432580 Hom.: 66 Cov.: 25 AF XY: 0.00800 AC XY: 5720 AN XY: 714664

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00499

Gnomad4 ASJ exome AF: 0.00586

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00528

Gnomad4 FIN exome AF: 0.00308

Gnomad4 NFE exome AF: 0.00917

Gnomad4 OTH exome AF: 0.00840

GnomAD4 genome AF: 0.00605 AC: 922 AN: 152336 Hom.: 1 Cov.: 32 AF XY: 0.00529 AC XY: 394 AN XY: 74494

Gnomad4 AFR AF: 0.00180

Gnomad4 AMR AF: 0.00497

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00540

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.00989

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00877 Hom.: 6

Bravo AF: 0.00578

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00919 AC: 79

ExAC AF: 0.00661 AC: 803

Asia WGS AF: 0.00115 AC: 5 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 19, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	KIFBP: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 15, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2017	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. -

KIFBP-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 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). -

Goldberg-Shprintzen syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	21
Dann	Benign	0.89
DEOGEN2	Benign	0.063	T;T;T
Eigen	Benign	-0.059
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T;T;T
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.0	N;.;.
REVEL	Benign	0.13
Sift	Benign	0.71	T;.;.
Sift4G	Benign	0.30	T;.;T
Polyphen		0.16	B;.;.
Vest4		0.77
MVP		0.48
MPC		0.54
ClinPred		0.019	T
GERP RS		5.1
Varity_R		0.28
gMVP		0.25

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: rs62625033; hg19: chr10-70760271;