rs730882150

chr10-69005119-C-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015634.4(KIFBP):c.599C>A(p.Ser200Ter) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.10

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 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	UniProt
KIFBP	NM_015634.4	c.599C>A	p.Ser200Ter	stop_gained	3/7	ENST00000361983.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIFBP	ENST00000361983.7	c.599C>A	p.Ser200Ter	stop_gained	3/7	1	NM_015634.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152054 Hom.: 0 Cov.: 32

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: 8 AN: 251244 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135826

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.: 0 Cov.: 28 AF XY: 0.0000635 AC XY: 46 AN XY: 724784

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: 8 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74278

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.: 0

Bravo AF: 0.0000642

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

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, 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 08, 2021	- -

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	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	41
Dann	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	A
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

Other links and lift over

dbSNP: rs730882150; hg19: chr10-70764875;