13-98810219-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting 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. D1735V) 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

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012893587).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome 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 gnomad4_exome. There are 533 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK9	NM_001366683.2	c.5203G>A	p.Asp1735Asn	missense_variant	Exon 46 of 53	ENST00000682017.1	NP_001353612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK9	ENST00000682017.1	c.5203G>A	p.Asp1735Asn	missense_variant	Exon 46 of 53		NM_001366683.2	ENSP00000507034.1

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

GnomAD3 exomes AF: 0.000951 AC: 237 AN: 249090 Hom.: 2 AF XY: 0.00102 AC XY: 138 AN XY: 135150

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 SAS exome AF: 0.00105

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

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000961

Gnomad4 ASJ exome AF: 0.00528

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000893

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000471

Gnomad4 OTH exome AF: 0.00152

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

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000779

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00125 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

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5206G>A (p.D1736N) alteration is located in exon 47 (coding exon 47) of the DOCK9 gene. This alteration results from a G to A substitution at nucleotide position 5206, causing the aspartic acid (D) at amino acid position 1736 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Benign	-0.55	T
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.5	.;N;.;D;D
REVEL	Benign	0.096
Sift	Uncertain	0.0080	.;D;.;D;D
Sift4G	Uncertain	0.027	.;D;D;T;.
Polyphen		0.92, 0.90	.;P;.;.;P
Vest4		0.69, 0.61
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs61745987; hg19: chr13-99462473;