rs61735441

Positions:

• chr17-6608421-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014804.3(KIAA0753):​c.1756A>G​(p.Lys586Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00893 in 1,568,062 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0091 (91 hom.)
• Consequence: KIAA0753 NM_014804.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.41

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004587382).
• BP6: Variant 17-6608421-T-C is Benign according to our data. Variant chr17-6608421-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 376793.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 = 0.00708 (1079/152326) while in subpopulation NFE AF= 0.00925 (629/68034). AF 95% confidence interval is 0.00865. There are 2 homozygotes in gnomad4. There are 527 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIAA0753	NM_014804.3	c.1756A>G	p.Lys586Glu	missense_variant	10/19	ENST00000361413.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIAA0753	ENST00000361413.8	c.1756A>G	p.Lys586Glu	missense_variant	10/19	1	NM_014804.3	P1

Frequencies

GnomAD3 genomes AF: 0.00709 AC: 1079 AN: 152208 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00924

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00711 AC: 1626 AN: 228834 Hom.: 8 AF XY: 0.00683 AC XY: 854 AN XY: 125032

Gnomad AFR exome AF: 0.00256

Gnomad AMR exome AF: 0.00403

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.0000661

Gnomad SAS exome AF: 0.000823

Gnomad FIN exome AF: 0.00921

Gnomad NFE exome AF: 0.00904

Gnomad OTH exome AF: 0.00676

GnomAD4 exome AF: 0.00912 AC: 12916 AN: 1415736 Hom.: 91 Cov.: 29 AF XY: 0.00892 AC XY: 6286 AN XY: 704438

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00401

Gnomad4 ASJ exome AF: 0.0247

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000853

Gnomad4 FIN exome AF: 0.0103

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00767

GnomAD4 genome AF: 0.00708 AC: 1079 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.00708 AC XY: 527 AN XY: 74484

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.00582

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.00925

Gnomad4 OTH AF: 0.00992

Alfa AF: 0.00912 Hom.: 9

Bravo AF: 0.00698

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00233 AC: 9

ESP6500EA AF: 0.00978 AC: 81

ExAC AF: 0.00684 AC: 827

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 26, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	KIAA0753: BP4, BS2 -

Orofaciodigital syndrome XV;C5561958:Joubert syndrome 38;C5561961:Short-rib thoracic dysplasia 21 without polydactyly Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 26, 2022

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0029	T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.47	T;T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-0.41	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.019	D;.
Sift4G	Benign	0.33	T;T
Polyphen		0.88	P;.
Vest4		0.20
MVP		0.58
MPC		0.51
ClinPred		0.011	T
GERP RS		4.0
Varity_R		0.075
gMVP		0.076

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs61735441; hg19: chr17-6511741;