NM_014804.3:c.2778A>G

Variant names:

• chr17-6589787-T-C
• rs61735435
• NM_014804.3:c.2778A>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.2778A>G​(p.Ile926Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.022 in 1,600,498 control chromosomes in the GnomAD database, including 481 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (36 hom., cov: 33)
  • Exomes 𝑓: 0.023 (445 hom.)
• Consequence: KIAA0753 NM_014804.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.376
• Publications: 5 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=0.0038268864).
• BP6: Variant 17-6589787-T-C is Benign according to our data. Variant chr17-6589787-T-C is described in ClinVar as Benign. ClinVar VariationId is 1667710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0155 (2358/152318) while in subpopulation SAS AF = 0.0329 (159/4832). AF 95% confidence interval is 0.0287. There are 36 homozygotes in GnomAd4. There are 1156 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 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.2778A>G	p.Ile926Met	missense	Exon 18 of 19	NP_055619.2	Q2KHM9-1
	KIAA0753	NM_001351225.2		c.1881A>G	p.Ile627Met	missense	Exon 18 of 19	NP_001338154.1	Q2KHM9-2
	KIAA0753	NR_147086.2		n.2584A>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.2778A>G	p.Ile926Met	missense	Exon 18 of 19	ENSP00000355250.3	Q2KHM9-1
	KIAA0753	ENST00000572370.5	TSL:2	c.1881A>G	p.Ile627Met	missense	Exon 17 of 18	ENSP00000460050.1	Q2KHM9-2
	KIAA0753	ENST00000576281.5	TSL:5	c.366A>G	p.Ile122Met	missense	Exon 3 of 4	ENSP00000460156.1	I3L341

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2357 AN: 152200 Hom.: 36 Cov.: 33

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0325

Gnomad FIN AF: 0.0267

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0215

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0185 AC: 4343 AN: 235284 AF XY: 0.0200

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.00557

Gnomad ASJ exome AF: 0.0366

Gnomad EAS exome AF: 0.0000584

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.0216

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.0227 AC: 32897 AN: 1448180 Hom.: 445 Cov.: 31 AF XY: 0.0229 AC XY: 16521 AN XY: 720372

African (AFR) AF: 0.00352 AC: 114 AN: 32420

American (AMR) AF: 0.00570 AC: 229 AN: 40158

Ashkenazi Jewish (ASJ) AF: 0.0376 AC: 954 AN: 25382

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39574

South Asian (SAS) AF: 0.0303 AC: 2527 AN: 83508

European-Finnish (FIN) AF: 0.0259 AC: 1379 AN: 53312

Middle Eastern (MID) AF: 0.0131 AC: 73 AN: 5582

European-Non Finnish (NFE) AF: 0.0238 AC: 26360 AN: 1108444

Other (OTH) AF: 0.0211 AC: 1260 AN: 59800

GnomAD4 genome AF: 0.0155 AC: 2358 AN: 152318 Hom.: 36 Cov.: 33 AF XY: 0.0155 AC XY: 1156 AN XY: 74484

African (AFR) AF: 0.00383 AC: 159 AN: 41566

American (AMR) AF: 0.00882 AC: 135 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.0329 AC: 159 AN: 4832

European-Finnish (FIN) AF: 0.0267 AC: 283 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0215 AC: 1466 AN: 68030

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.0202 Hom.: 120

Bravo AF: 0.0132

TwinsUK AF: 0.0278 AC: 103

ALSPAC AF: 0.0210 AC: 81

ESP6500AA AF: 0.00551 AC: 21

ESP6500EA AF: 0.0247 AC: 203

ExAC AF: 0.0185 AC: 2230

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0214

EpiControl AF: 0.0195

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.38
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.042
Sift	Benign	0.082	T
Sift4G	Benign	0.17	T
Polyphen		0.26	B
Vest4		0.11
MPC		0.28
ClinPred		0.022	T
GERP RS		-7.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.057
gMVP		0.40
Mutation Taster		=98/2	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: rs61735435; hg19: chr17-6493107;