NM_203447.4:c.187G>A

Variant names:

• chr9-286491-G-A
• rs3209441
• NM_203447.4:c.187G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_203447.4(DOCK8):​c.187G>A​(p.Asp63Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,776 control chromosomes in the GnomAD database, including 22,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D63D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1334 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21012 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 9.60
• Publications: 29 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, Genomics England PanelApp, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001942724).
• BP6: Variant 9-286491-G-A is Benign according to our data. Variant chr9-286491-G-A is described in ClinVar as Benign. ClinVar VariationId is 137156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

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.187G>A	p.Asp63Asn	missense	Exon 3 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.-18G>A		5_prime_UTR	Exon 2 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.-18G>A		5_prime_UTR	Exon 2 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.187G>A	p.Asp63Asn	missense	Exon 3 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.-18G>A		5_prime_UTR	Exon 2 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.-18G>A		5_prime_UTR	Exon 3 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.114 AC: 17388 AN: 152094 Hom.: 1335 Cov.: 32

Gnomad AFR AF: 0.0306

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.0980

Gnomad ASJ AF: 0.0991

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.122 AC: 30733 AN: 251134 AF XY: 0.128

Gnomad AFR exome AF: 0.0279

Gnomad AMR exome AF: 0.0701

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.00141

Gnomad FIN exome AF: 0.118

Gnomad NFE exome AF: 0.173

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.163 AC: 237665 AN: 1461564 Hom.: 21012 Cov.: 31 AF XY: 0.162 AC XY: 117891 AN XY: 727078

African (AFR) AF: 0.0251 AC: 839 AN: 33456

American (AMR) AF: 0.0734 AC: 3280 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 3031 AN: 26128

East Asian (EAS) AF: 0.000706 AC: 28 AN: 39688

South Asian (SAS) AF: 0.119 AC: 10257 AN: 86244

European-Finnish (FIN) AF: 0.120 AC: 6398 AN: 53410

Middle Eastern (MID) AF: 0.109 AC: 628 AN: 5760

European-Non Finnish (NFE) AF: 0.184 AC: 204536 AN: 1111804

Other (OTH) AF: 0.144 AC: 8668 AN: 60376

GnomAD4 genome AF: 0.114 AC: 17378 AN: 152212 Hom.: 1334 Cov.: 32 AF XY: 0.110 AC XY: 8180 AN XY: 74412

African (AFR) AF: 0.0305 AC: 1265 AN: 41542

American (AMR) AF: 0.0978 AC: 1495 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0991 AC: 344 AN: 3472

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5186

South Asian (SAS) AF: 0.116 AC: 558 AN: 4818

European-Finnish (FIN) AF: 0.111 AC: 1177 AN: 10594

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.177 AC: 12007 AN: 67994

Other (OTH) AF: 0.113 AC: 239 AN: 2110

Alfa AF: 0.155 Hom.: 9988

Bravo AF: 0.109

TwinsUK AF: 0.189 AC: 700

ALSPAC AF: 0.186 AC: 716

ESP6500AA AF: 0.0315 AC: 139

ESP6500EA AF: 0.176 AC: 1513

ExAC AF: 0.123 AC: 14953

Asia WGS AF: 0.0480 AC: 169 AN: 3478

EpiCase AF: 0.173

EpiControl AF: 0.184

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	Combined immunodeficiency due to DOCK8 deficiency (1)
-	-	1	not provided (2)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.6
PrimateAI	Uncertain	0.62	T
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.30
ClinPred		0.014	T
GERP RS		5.5
Varity_R		0.95
gMVP		0.71
Mutation Taster		=239/61	polymorphism (auto)

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: rs3209441; hg19: chr9-286491; COSMIC: COSV66634213;