Variant rs730882150 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_015634.4(KIFBP):c.599C>A(p.Ser200*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000746 in 1,608,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

KIFBP
NM_015634.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.10

Variant links:

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]

KIFBP links:

KIFBP (HGNC:):

KIFBP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-69005119-C-A is Pathogenic according to our data. Variant chr10-69005119-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 183145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIFBP	NM_015634.4 linkuse as main transcript	c.599C>A	p.Ser200*	stop_gained	3/7	ENST00000361983.7	NP_056449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIFBP	ENST00000361983.7 linkuse as main transcript	c.599C>A	p.Ser200*	stop_gained	3/7	1	NM_015634.4	ENSP00000354848.4		Q96EK5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152054

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251244

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000769

AC:

112

AN:

1456070

Hom.:

Cov.:

AF XY:

0.0000635

AC XY:

AN XY:

724784

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000958

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152054

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000575

Hom.:

Bravo

AF:

0.0000642

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Goldberg-Shprintzen syndrome

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This nonsense variant found in exon 3 of 7 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a homozygous change in two siblings with Goldberg-Shprintzen syndrome (GOSHS) (PMID: 23427148). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (9/282480) and thus is presumed to be rare. Based on the available evidence, the c.599C>A (p.Ser200Ter) variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 08, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 15, 2013	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Mar 13, 2024	The heterozygous p.Ser200Ter variant in KIFBP was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar ID: 300283), in two siblings with congenital fibrosis of the extraocular muscles, hearing impairment, developmental delays, cognitive impairment, scoliosis, Hirschsprung disease, and dysmorphic facial features, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). Familial genome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 300283). We believe this is a possible phenotype expansion for Goldberg-Shprintzen megacolon syndrome. The p.Ser200Ter variant in KIFBP has been previously reported in two siblings with Goldberg-Shprintzen megacolon syndrome and segregated with disease in this family (PMID: 23427148), but has been identified in 0.007% (9/128934) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs730882150). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. These two affected siblings were homozygotes, which increases the likelihood that the p.Ser200Ter variant is pathogenic (PMID: 23427148). This variant has also been reported in ClinVar (Variation ID: 183145) and has been interpreted as pathogenic by Fulgent Genetics, Eurofins NTD LLC, and OMIM. RT-PCR analysis performed on affected tissue showed significantly reduced mRNA and protein expression versus wild-type (PMID: 23427148). This nonsense variant leads to a premature termination codon at position 200, which is predicted to lead to a truncated or absent protein. Loss of function of the KIFBP gene is an established disease mechanism in Goldberg-Shprintzen megacolon syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Goldberg-Shprintzen megacolon syndrome. ACMG/AMP Criteria applied: PVS1, PS3_Moderate, PM2_Supporting, PM3_Supporting (Richards 2015). -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease (Drvillon et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32939943, 28277559, 23427148) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.89

Vest4

0.21

GERP RS

5.8

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over