Genetic Variant NM_001366683.2:c.4636G>T (chr13-98829756-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001366683.2(DOCK9):c.4636G>T(p.Val1546Phe) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000207 in 1,448,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1546I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

DOCK9
NM_001366683.2 missense, splice_region

Scores

Splicing: ADA: 0.9983

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.83

Publications

0 publications found

Variant links:

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 links:

DOCK9-AS1 (HGNC:40672): (DOCK9 antisense RNA 1)

DOCK9-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOCK9	NM_001366683.2	MANE Select	c.4636G>T	p.Val1546Phe	missense splice_region	Exon 42 of 53	NP_001353612.1	A0A804HIE8
DOCK9	NM_001366681.2		c.4636G>T	p.Val1546Phe	missense splice_region	Exon 42 of 55	NP_001353610.1
DOCK9	NM_001366684.2		c.4636G>T	p.Val1546Phe	missense splice_region	Exon 42 of 54	NP_001353613.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DOCK9	ENST00000682017.1	MANE Select	c.4636G>T	p.Val1546Phe	missense splice_region	Exon 42 of 53	ENSP00000507034.1	A0A804HIE8
DOCK9	ENST00000903387.1		c.4636G>T	p.Val1546Phe	missense splice_region	Exon 43 of 54	ENSP00000573446.1
DOCK9	ENST00000448493.7	TSL:5	c.4603G>T	p.Val1535Phe	missense splice_region	Exon 42 of 53	ENSP00000401958.4	A0A088AWN3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000207

AC:

AN:

1448890

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

719122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33316

American (AMR)

AF:

0.00

AC:

AN:

43158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25824

East Asian (EAS)

AF:

0.00

AC:

AN:

39380

South Asian (SAS)

AF:

0.00

AC:

AN:

83518

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52722

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1105274

Other (OTH)

AF:

0.0000167

AC:

AN:

59946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.59

MetaSVM

Uncertain

0.10

PhyloP100

3.8

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.5

REVEL

Benign

0.27

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.37

Vest4

0.79

MVP

0.70

MPC

0.86

ClinPred

0.98

GERP RS

4.7

PromoterAI

-0.041

Neutral

(source)

gMVP

0.97

Mutation Taster

=10/90

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.23

Position offset: -17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over