rs61735441

Variant names:

• chr17-6608421-T-C
• rs61735441
• NM_014804.3:c.1756A>G

Variant summary

Our verdict is Benign. The variant received -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. 12/20 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:6
• Conservation: PhyloP100: 2.41
• Publications: 3 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=0.004587382).
• BP6: Variant 17-6608421-T-C is Benign according to our data. Variant chr17-6608421-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.1756A>G	p.Lys586Glu	missense	Exon 10 of 19	NP_055619.2	Q2KHM9-1
	KIAA0753	NM_001351225.2		c.859A>G	p.Lys287Glu	missense	Exon 10 of 19	NP_001338154.1	Q2KHM9-2
	KIAA0753	NR_147086.2		n.1562A>G		non_coding_transcript_exon	Exon 8 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIAA0753	ENST00000361413.8	TSL:1 MANE Select	c.1756A>G	p.Lys586Glu	missense	Exon 10 of 19	ENSP00000355250.3	Q2KHM9-1
	KIAA0753	ENST00000572370.5	TSL:2	c.859A>G	p.Lys287Glu	missense	Exon 9 of 18	ENSP00000460050.1	Q2KHM9-2
	ENSG00000282936	ENST00000634965.3	TSL:6	c.*2706A>G		3_prime_UTR	Exon 10 of 19	ENSP00000499350.1	A0A590UJ96

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

GnomAD2 exomes AF: 0.00711 AC: 1626 AN: 228834 AF XY: 0.00683

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 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

African (AFR) AF: 0.00161 AC: 51 AN: 31750

American (AMR) AF: 0.00401 AC: 164 AN: 40866

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 618 AN: 25018

East Asian (EAS) AF: 0.00 AC: 0 AN: 36984

South Asian (SAS) AF: 0.000853 AC: 69 AN: 80892

European-Finnish (FIN) AF: 0.0103 AC: 538 AN: 52254

Middle Eastern (MID) AF: 0.000536 AC: 3 AN: 5596

European-Non Finnish (NFE) AF: 0.0102 AC: 11029 AN: 1084510

Other (OTH) AF: 0.00767 AC: 444 AN: 57866

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

African (AFR) AF: 0.00219 AC: 91 AN: 41568

American (AMR) AF: 0.00582 AC: 89 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0297 AC: 103 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4828

European-Finnish (FIN) AF: 0.0103 AC: 109 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00925 AC: 629 AN: 68034

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00878 Hom.: 21

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	-	1	Orofaciodigital syndrome XV;C5561958:Joubert syndrome 38;C5561961:Short-rib thoracic dysplasia 21 without polydactyly (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.41	T
PhyloP100		2.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.019	D
Sift4G	Benign	0.33	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
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs61735441; hg19: chr17-6511741;