rs62625033

Variant names:

• chr10-69000515-T-C
• rs62625033
• NM_015634.4:c.518T>C

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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:12
• Conservation: PhyloP100: 6.47
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• Goldberg-Shprintzen syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 66 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIFBP	NM_015634.4	c.518T>C	p.Met173Thr	missense_variant	Exon 2 of 7	ENST00000361983.7	NP_056449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIFBP	ENST00000361983.7	c.518T>C	p.Met173Thr	missense_variant	Exon 2 of 7	1	NM_015634.4	ENSP00000354848.4

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

GnomAD2 exomes AF: 0.00650 AC: 1632 AN: 251074 AF XY: 0.00669

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 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

African (AFR) AF: 0.00140 AC: 46 AN: 32868

American (AMR) AF: 0.00499 AC: 223 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00586 AC: 152 AN: 25928

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39456

South Asian (SAS) AF: 0.00528 AC: 452 AN: 85674

European-Finnish (FIN) AF: 0.00308 AC: 164 AN: 53244

Middle Eastern (MID) AF: 0.00808 AC: 46 AN: 5690

European-Non Finnish (NFE) AF: 0.00917 AC: 9959 AN: 1085658

Other (OTH) AF: 0.00840 AC: 499 AN: 59392

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

African (AFR) AF: 0.00180 AC: 75 AN: 41582

American (AMR) AF: 0.00497 AC: 76 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00540 AC: 26 AN: 4816

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00989 AC: 673 AN: 68026

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.00865 Hom.: 19

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Aug 08, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jun 15, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:5

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KIFBP: BS2 -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 19, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KIFBP-related disorder Benign:1

Sep 26, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.
PhyloP100		6.5
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
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs62625033; hg19: chr10-70760271;