17-6608421-T-C

Position:

chr17-6608421-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.41

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	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 linkuse as main transcript	c.1756A>G	p.Lys586Glu	missense_variant	10/19	1	NM_014804.3	P1	Q2KHM9-1

Frequencies

GnomAD3 genomes

AF:

0.00709

AC:

1079

AN:

152208

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00683

AC XY:

854

AN XY:

125032

show subpopulations

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.:

Cov.:

AF XY:

0.00892

AC XY:

6286

AN XY:

704438

show subpopulations

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.:

Cov.:

AF XY:

0.00708

AC XY:

527

AN XY:

74484

show subpopulations

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.:

Bravo

AF:

0.00698

TwinsUK

AF:

0.0119

AC:

ALSPAC

AF:

0.00778

AC:

ESP6500AA

AF:

0.00233

AC:

ESP6500EA

AF:

0.00978

AC:

ExAC

AF:

0.00684

AC:

827

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0029

T;.

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.47

T;T

MetaRNN

Benign

0.0046

T;T

MetaSVM

Benign

-0.41

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.36

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over