rs150742426

Variant names:

• chr9-289557-G-A
• rs150742426
• NM_203447.4:c.380G>A
• DOCK8 p.Arg127His

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.380G>A​(p.Arg127His) variant causes a missense change. The variant allele was found at a frequency of 0.00289 in 1,612,154 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts 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. R127C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (13 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 6.11
• Publications: 6 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: Ambry Genetics, Orphanet, G2P, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• 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=0.0122380555).
• BP6: Variant 9-289557-G-A is Benign according to our data. Variant chr9-289557-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 366538.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0019 (290/152268) while in subpopulation NFE AF = 0.00337 (229/68006). AF 95% confidence interval is 0.00301. There are 1 homozygotes in GnomAd4. There are 118 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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.380G>A	p.Arg127His	missense	Exon 4 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.176G>A	p.Arg59His	missense	Exon 3 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.176G>A	p.Arg59His	missense	Exon 3 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.380G>A	p.Arg127His	missense	Exon 4 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.176G>A	p.Arg59His	missense	Exon 3 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.176G>A	p.Arg59His	missense	Exon 4 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.00190 AC: 289 AN: 152150 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00200 AC: 503 AN: 251228 AF XY: 0.00197

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00366

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00300 AC: 4373 AN: 1459886 Hom.: 13 Cov.: 31 AF XY: 0.00292 AC XY: 2118 AN XY: 726190

African (AFR) AF: 0.000389 AC: 13 AN: 33432

American (AMR) AF: 0.000604 AC: 27 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.000501 AC: 43 AN: 85772

European-Finnish (FIN) AF: 0.00122 AC: 65 AN: 53278

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5724

European-Non Finnish (NFE) AF: 0.00370 AC: 4106 AN: 1110966

Other (OTH) AF: 0.00166 AC: 100 AN: 60276

GnomAD4 genome AF: 0.00190 AC: 290 AN: 152268 Hom.: 1 Cov.: 33 AF XY: 0.00158 AC XY: 118 AN XY: 74466

African (AFR) AF: 0.000674 AC: 28 AN: 41548

American (AMR) AF: 0.000850 AC: 13 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00337 AC: 229 AN: 68006

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00284 Hom.: 1

Bravo AF: 0.00176

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	1	2	Combined immunodeficiency due to DOCK8 deficiency (3)
-	-	1	DOCK8-related disorder (1)
-	-	1	Intellectual disability (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.9	L
PhyloP100		6.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.13
Sift	Benign	0.088	T
Sift4G	Benign	0.12	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.21
gMVP		0.46
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: rs150742426;

hg19: chr9-289557;

COSMIC: COSV108224237;

COSMIC: COSV108224237;