rs141632537

chr17-6624826-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2 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:3
• Conservation: PhyloP100: 2.35

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0753	NM_014804.3	c.754C>T	p.Arg252Cys	missense_variant	4/19	ENST00000361413.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0753	ENST00000361413.8	c.754C>T	p.Arg252Cys	missense_variant	4/19	1	NM_014804.3	P1

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

GnomAD3 exomes AF: 0.000867 AC: 149 AN: 171824 Hom.: 0 AF XY: 0.000602 AC XY: 55 AN XY: 91324

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 SAS exome AF: 0.0000421

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

Gnomad4 AFR exome AF: 0.0109

Gnomad4 AMR exome AF: 0.000782

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000534

Gnomad4 SAS exome AF: 0.0000249

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000217

Gnomad4 OTH exome AF: 0.000771

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

Gnomad4 AFR AF: 0.0105

Gnomad4 AMR AF: 0.00189

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: 0.000946

Alfa AF: 0.000569 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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 19, 2017	- -

KIAA0753-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2019

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 v4.3

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
MutationTaster	Benign	1.0	N;N;N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs141632537; hg19: chr17-6528146; COSMIC: COSV63817272; COSMIC: COSV63817272;