NM_001366683.2:c.5203G>A

Variant names:

• chr13-98810219-C-T
• rs61745987
• NM_001366683.2:c.5203G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001366683.2(DOCK9):​c.5203G>A​(p.Asp1735Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000698 in 1,613,888 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1735G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00077 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (3 hom.)
• Consequence: DOCK9 NM_001366683.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.60
• Publications: 4 publications found

Genes affected

DOCK9 (HGNC:14132): (dedicator of cytokinesis 9) Enables cadherin binding activity. Predicted to be involved in positive regulation of GTPase activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

DOCK9 Gene-Disease associations (from GenCC):

• keratoconus

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012893587).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000691 (1010/1461610) while in subpopulation MID AF = 0.0196 (113/5768). AF 95% confidence interval is 0.0167. There are 3 homozygotes in GnomAdExome4. There are 533 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 117 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366683.2. 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
	DOCK9	NM_001366683.2	MANE Select	c.5203G>A	p.Asp1735Asn	missense	Exon 46 of 53	NP_001353612.1	A0A804HIE8
	DOCK9	NM_001366681.2		c.5272G>A	p.Asp1758Asn	missense	Exon 47 of 55	NP_001353610.1
	DOCK9	NM_001366684.2		c.5272G>A	p.Asp1758Asn	missense	Exon 47 of 54	NP_001353613.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK9	ENST00000682017.1	MANE Select	c.5203G>A	p.Asp1735Asn	missense	Exon 46 of 53	ENSP00000507034.1	A0A804HIE8
	DOCK9	ENST00000903387.1		c.5203G>A	p.Asp1735Asn	missense	Exon 47 of 54	ENSP00000573446.1
	DOCK9	ENST00000448493.7	TSL:5	c.5170G>A	p.Asp1724Asn	missense	Exon 46 of 53	ENSP00000401958.4	A0A088AWN3

Frequencies

GnomAD3 genomes AF: 0.000775 AC: 118 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000951 AC: 237 AN: 249090 AF XY: 0.00102

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000927

Gnomad ASJ exome AF: 0.00597

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000894

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000691 AC: 1010 AN: 1461610 Hom.: 3 Cov.: 30 AF XY: 0.000733 AC XY: 533 AN XY: 727090

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.000961 AC: 43 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00528 AC: 138 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000893 AC: 77 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53314

Middle Eastern (MID) AF: 0.0196 AC: 113 AN: 5768

European-Non Finnish (NFE) AF: 0.000471 AC: 524 AN: 1111868

Other (OTH) AF: 0.00152 AC: 92 AN: 60372

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.000792 AC XY: 59 AN XY: 74454

African (AFR) AF: 0.000289 AC: 12 AN: 41564

American (AMR) AF: 0.000981 AC: 15 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68014

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00123 Hom.: 0

Bravo AF: 0.000835

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.000893 AC: 108

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.47
CADD	Pathogenic	26
DANN	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.55	T
PhyloP100		4.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.096
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.027	D
Polyphen		0.92	P
Vest4		0.69
MVP		0.54
MPC		0.73
ClinPred		0.085	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.85
Mutation Taster		=64/36	polymorphism

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: rs61745987; hg19: chr13-99462473;