rs41279644

Positions:

• chr10-69016311-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015634.4(KIFBP):​c.1761T>C​(p.Pro587=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00604 in 1,608,528 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (38 hom.)
• Consequence: KIFBP NM_015634.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.437

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 10-69016311-T-C is Benign according to our data. Variant chr10-69016311-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 158695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-69016311-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.437 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0051 (777/152348) while in subpopulation NFE AF= 0.00611 (416/68032). AF 95% confidence interval is 0.00563. There are 7 homozygotes in gnomad4. There are 448 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIFBP	NM_015634.4	c.1761T>C	p.Pro587=	synonymous_variant	7/7	ENST00000361983.7
KIFBP	XM_017016067.2	c.963T>C	p.Pro321=	synonymous_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIFBP	ENST00000361983.7	c.1761T>C	p.Pro587=	synonymous_variant	7/7	1	NM_015634.4	P1

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 778 AN: 152230 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000892

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00613

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00585 AC: 1444 AN: 246692 Hom.: 8 AF XY: 0.00585 AC XY: 782 AN XY: 133640

Gnomad AFR exome AF: 0.000681

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.000309

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00196

Gnomad FIN exome AF: 0.0261

Gnomad NFE exome AF: 0.00649

Gnomad OTH exome AF: 0.00404

GnomAD4 exome AF: 0.00613 AC: 8932 AN: 1456180 Hom.: 38 Cov.: 32 AF XY: 0.00595 AC XY: 4308 AN XY: 724328

Gnomad4 AFR exome AF: 0.000908

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.000310

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00227

Gnomad4 FIN exome AF: 0.0237

Gnomad4 NFE exome AF: 0.00641

Gnomad4 OTH exome AF: 0.00394

GnomAD4 genome AF: 0.00510 AC: 777 AN: 152348 Hom.: 7 Cov.: 32 AF XY: 0.00601 AC XY: 448 AN XY: 74508

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0250

Gnomad4 NFE AF: 0.00611

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00490 Hom.: 2

Bravo AF: 0.00327

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 11, 2020	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	KIFBP: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Goldberg-Shprintzen syndrome Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.7
DANN	Benign	0.66

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: rs41279644; hg19: chr10-70776067;