rs752659088

Variant names:

• chr17-6624770-G-A
• rs752659088
• NM_014804.3:c.810C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP5 BP4

The NM_001351225.2(KIAA0753):​c.-425C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 1,406,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: KIAA0753 NM_001351225.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1 B:1
• Conservation: PhyloP100: -0.499
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PP5: Variant 17-6624770-G-A is Pathogenic according to our data. Variant chr17-6624770-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 558755.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001351225.2. 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.810C>T	p.Tyr270Tyr	synonymous	Exon 4 of 19	NP_055619.2	Q2KHM9-1
	KIAA0753	NM_001351225.2		c.-425C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 19	NP_001338154.1	Q2KHM9-2
	KIAA0753	NM_001351225.2		c.-425C>T		5_prime_UTR	Exon 4 of 19	NP_001338154.1	Q2KHM9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0753	ENST00000361413.8	TSL:1 MANE Select	c.810C>T	p.Tyr270Tyr	synonymous	Exon 4 of 19	ENSP00000355250.3	Q2KHM9-1
	KIAA0753	ENST00000572370.5	TSL:2	c.-107C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 18	ENSP00000460050.1	Q2KHM9-2
	KIAA0753	ENST00000572370.5	TSL:2	c.-107C>T		5_prime_UTR	Exon 3 of 18	ENSP00000460050.1	Q2KHM9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000650 AC: 11 AN: 169322 AF XY: 0.0000778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000126

Gnomad NFE exome AF: 0.0000293

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000263 AC: 37 AN: 1406662 Hom.: 0 Cov.: 30 AF XY: 0.0000259 AC XY: 18 AN XY: 694570

African (AFR) AF: 0.00 AC: 0 AN: 32336

American (AMR) AF: 0.0000273 AC: 1 AN: 36658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25382

East Asian (EAS) AF: 0.00 AC: 0 AN: 36990

South Asian (SAS) AF: 0.000313 AC: 25 AN: 79962

European-Finnish (FIN) AF: 0.0000605 AC: 3 AN: 49592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000740 AC: 8 AN: 1081764

Other (OTH) AF: 0.00 AC: 0 AN: 58276

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	1	not provided (4)
1	-	-	Jeune thoracic dystrophy (1)
1	-	-	Jeune thoracic dystrophy;C5979921:Joubert syndrome (1)
1	-	-	Orofaciodigital syndrome XV (1)
1	-	-	Orofaciodigital syndrome XV;C5561958:Joubert syndrome 38;C5561961:Short-rib thoracic dysplasia 21 without polydactyly (1)
1	-	-	Short-rib thoracic dysplasia 21 without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	5.5
DANN	Benign	0.56
PhyloP100		-0.50

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: rs752659088; hg19: chr17-6528090; COSMIC: COSV107466038; COSMIC: COSV107466038;