17-6624826-G-A

Variant names:

• chr17-6624826-G-A
• rs141632537
• NM_014804.3:c.754C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_014804.3(KIAA0753):​c.754C>T​(p.Arg252Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000729 in 1,561,708 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R252H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: KIAA0753 NM_014804.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.35
• Publications: 5 publications found

Genes affected

KIAA0753 (HGNC:29110): (KIAA0753) This gene encodes a subunit of a protein complex that regulates ciliogenesis and cilia maintenance. The encoded protein has also been shown to regulate centriolar duplication. Mutations in this gene cause an orofaciodigital syndrome and a form of Joubert syndrome in human patients. [provided by RefSeq, May 2017]

KIAA0753 Gene-Disease associations (from GenCC):

• orofaciodigital syndrome XV

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Franklin by Genoox
• orofaciodigital syndrome type 6

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000282936 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064225495).
• BP6: Variant 17-6624826-G-A is Benign according to our data. Variant chr17-6624826-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0031 (472/152268) while in subpopulation AFR AF = 0.0105 (435/41532). AF 95% confidence interval is 0.00966. There are 0 homozygotes in GnomAd4. There are 209 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014804.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0753	NM_014804.3	MANE Select	c.754C>T	p.Arg252Cys	missense	Exon 4 of 19	NP_055619.2
	KIAA0753	NM_001351225.2		c.-481C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 19	NP_001338154.1
	KIAA0753	NR_147088.2		n.897C>T		non_coding_transcript_exon	Exon 4 of 18

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0753	ENST00000361413.8	TSL:1 MANE Select	c.754C>T	p.Arg252Cys	missense	Exon 4 of 19	ENSP00000355250.3
	KIAA0753	ENST00000572370.5	TSL:2	c.-163C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 18	ENSP00000460050.1
	KIAA0753	ENST00000576823.1	TSL:4	n.407C>T		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 471 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

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: 0.000956

GnomAD2 exomes AF: 0.000867 AC: 149 AN: 171824 AF XY: 0.000602

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.000922

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000473 AC: 666 AN: 1409440 Hom.: 1 Cov.: 30 AF XY: 0.000412 AC XY: 287 AN XY: 696116

African (AFR) AF: 0.0109 AC: 353 AN: 32502

American (AMR) AF: 0.000782 AC: 29 AN: 37084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25414

East Asian (EAS) AF: 0.0000534 AC: 2 AN: 37440

South Asian (SAS) AF: 0.0000249 AC: 2 AN: 80196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.000217 AC: 235 AN: 1082956

Other (OTH) AF: 0.000771 AC: 45 AN: 58354

GnomAD4 genome AF: 0.00310 AC: 472 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74456

African (AFR) AF: 0.0105 AC: 435 AN: 41532

American (AMR) AF: 0.00189 AC: 29 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68022

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00111 Hom.: 1

Bravo AF: 0.00368

ESP6500AA AF: 0.00779 AC: 30

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000668 AC: 76

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 19, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Sep 02, 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.

KIAA0753-related disorder Benign:1

Sep 18, 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).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.088
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0064	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.4
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.073
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.050	T
Polyphen		1.0	D
Vest4		0.35
MVP		0.33
MPC		0.29
ClinPred		0.029	T
GERP RS		2.9
Varity_R		0.082
gMVP		0.034
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141632537; hg19: chr17-6528146; COSMIC: COSV63817272; COSMIC: COSV63817272;