rs151094543

Variant names:

• chr9-396872-A-G
• rs151094543
• NM_203447.4:c.3058A>G
• DOCK8 p.Ile1020Val

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_203447.4(DOCK8):​c.3058A>G​(p.Ile1020Val) variant causes a missense change. The variant allele was found at a frequency of 0.00047 in 1,614,110 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1020M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (6 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 3.75
• Publications: 5 publications found

Genes affected

DOCK8 (HGNC:19191): (dedicator of cytokinesis 8) This gene encodes a member of the DOCK180 family of guanine nucleotide exchange factors. Guanine nucleotide exchange factors interact with Rho GTPases and are components of intracellular signaling networks. Mutations in this gene result in the autosomal recessive form of the hyper-IgE syndrome. Alternatively spliced transcript variants encoding different isoforms have been described.[provided by RefSeq, Jun 2010]

DOCK8 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to DOCK8 deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0324623).
• BP6: Variant 9-396872-A-G is Benign according to our data. Variant chr9-396872-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218873.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000473 (72/152276) while in subpopulation AMR AF = 0.00209 (32/15298). AF 95% confidence interval is 0.00152. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203447.4. 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
	DOCK8	NM_203447.4	MANE Select	c.3058A>G	p.Ile1020Val	missense	Exon 25 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.2854A>G	p.Ile952Val	missense	Exon 24 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.2758A>G	p.Ile920Val	missense	Exon 23 of 46	NP_001177387.1	Q8NF50-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK8	ENST00000432829.7	TSL:1 MANE Select	c.3058A>G	p.Ile1020Val	missense	Exon 25 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.2758A>G	p.Ile920Val	missense	Exon 23 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.2758A>G	p.Ile920Val	missense	Exon 24 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000481 AC: 121 AN: 251428 AF XY: 0.000552

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000536

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000469 AC: 686 AN: 1461834 Hom.: 6 Cov.: 32 AF XY: 0.000495 AC XY: 360 AN XY: 727214

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000671 AC: 30 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000707 AC: 61 AN: 86256

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53382

Middle Eastern (MID) AF: 0.00954 AC: 55 AN: 5768

European-Non Finnish (NFE) AF: 0.000438 AC: 487 AN: 1111994

Other (OTH) AF: 0.000646 AC: 39 AN: 60394

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74464

African (AFR) AF: 0.0000963 AC: 4 AN: 41548

American (AMR) AF: 0.00209 AC: 32 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000965 Hom.: 2

Bravo AF: 0.000676

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Combined immunodeficiency due to DOCK8 deficiency (1)
-	1	-	DOCK8-related disorder (1)
-	-	1	not specified (1)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.18
Eigen_PC	Benign	0.017
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.7
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.034
Sift	Benign	0.19	T
Sift4G	Benign	0.23	T
Varity_R		0.061
gMVP		0.20
Mutation Taster		=89/11	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs151094543;

hg19: chr9-396872;