rs1443417

Variant names:

• chr17-6589878-T-C
• rs1443417
• NM_014804.3:c.2687A>G

Your query was ambiguous. Multiple possible variants found:

• chr17-6589878-T-C
• chr17-6589878-T-A
• chr17-6589878-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014804.3(KIAA0753):​c.2687A>G​(p.Gln896Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 1,612,958 control chromosomes in the GnomAD database, including 285,159 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q896W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.64 (32131 hom., cov: 32)
  • Exomes 𝑓: 0.59 (253028 hom.)
• Consequence: KIAA0753 NM_014804.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.73
• Publications: 41 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0560783E-6).
• BP6: Variant 17-6589878-T-C is Benign according to our data. Variant chr17-6589878-T-C is described in ClinVar as Benign. ClinVar VariationId is 1236419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.771 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0753	NM_014804.3	MANE Select	c.2687A>G	p.Gln896Arg	missense	Exon 18 of 19	NP_055619.2	Q2KHM9-1
	KIAA0753	NM_001351225.2		c.1790A>G	p.Gln597Arg	missense	Exon 18 of 19	NP_001338154.1	Q2KHM9-2
	KIAA0753	NR_147086.2		n.2493A>G		non_coding_transcript_exon	Exon 16 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0753	ENST00000361413.8	TSL:1 MANE Select	c.2687A>G	p.Gln896Arg	missense	Exon 18 of 19	ENSP00000355250.3	Q2KHM9-1
	KIAA0753	ENST00000572370.5	TSL:2	c.1790A>G	p.Gln597Arg	missense	Exon 17 of 18	ENSP00000460050.1	Q2KHM9-2
	KIAA0753	ENST00000576281.5	TSL:5	c.275A>G	p.Gln92Arg	missense	Exon 3 of 4	ENSP00000460156.1	I3L341

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97690 AN: 151938 Hom.: 32078 Cov.: 32

Gnomad AFR AF: 0.778

Gnomad AMI AF: 0.664

Gnomad AMR AF: 0.680

Gnomad ASJ AF: 0.511

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.638

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.609

GnomAD2 exomes AF: 0.622 AC: 154948 AN: 248926 AF XY: 0.614

Gnomad AFR exome AF: 0.785

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.511

Gnomad EAS exome AF: 0.702

Gnomad FIN exome AF: 0.554

Gnomad NFE exome AF: 0.570

Gnomad OTH exome AF: 0.608

GnomAD4 exome AF: 0.585 AC: 855263 AN: 1460902 Hom.: 253028 Cov.: 42 AF XY: 0.585 AC XY: 425275 AN XY: 726752

African (AFR) AF: 0.784 AC: 26198 AN: 33434

American (AMR) AF: 0.737 AC: 32894 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 13411 AN: 26110

East Asian (EAS) AF: 0.725 AC: 28744 AN: 39660

South Asian (SAS) AF: 0.635 AC: 54735 AN: 86138

European-Finnish (FIN) AF: 0.553 AC: 29518 AN: 53400

Middle Eastern (MID) AF: 0.593 AC: 3416 AN: 5764

European-Non Finnish (NFE) AF: 0.567 AC: 630266 AN: 1111414

Other (OTH) AF: 0.598 AC: 36081 AN: 60374

GnomAD4 genome AF: 0.643 AC: 97792 AN: 152056 Hom.: 32131 Cov.: 32 AF XY: 0.644 AC XY: 47835 AN XY: 74330

African (AFR) AF: 0.778 AC: 32293 AN: 41488

American (AMR) AF: 0.680 AC: 10398 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 1775 AN: 3472

East Asian (EAS) AF: 0.716 AC: 3696 AN: 5162

South Asian (SAS) AF: 0.637 AC: 3064 AN: 4810

European-Finnish (FIN) AF: 0.542 AC: 5724 AN: 10566

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.570 AC: 38761 AN: 67962

Other (OTH) AF: 0.613 AC: 1296 AN: 2114

Alfa AF: 0.593 Hom.: 92137

Bravo AF: 0.659

TwinsUK AF: 0.565 AC: 2094

ALSPAC AF: 0.572 AC: 2205

ESP6500AA AF: 0.779 AC: 2960

ESP6500EA AF: 0.574 AC: 4733

ExAC AF: 0.622 AC: 75185

Asia WGS AF: 0.697 AC: 2429 AN: 3478

EpiCase AF: 0.565

EpiControl AF: 0.561

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Joubert syndrome 38 (1)
-	-	1	Orofaciodigital syndrome XV (1)
-	-	1	Short-rib thoracic dysplasia 21 without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	11
DANN	Benign	0.12
DEOGEN2	Benign	0.00093	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.16	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.7
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.84	N
REVEL	Benign	0.014
Sift	Benign	0.35	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.081
ClinPred		0.0029	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.015
gMVP		0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs1443417; hg19: chr17-6493198; COSMIC: COSV63816774;