NM_203447.4:c.1238A>G

Variant names:

• chr9-334337-A-G
• rs10970979
• NM_203447.4:c.1238A>G

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.1238A>G​(p.Asn413Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,613,726 control chromosomes in the GnomAD database, including 67,987 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N413G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.26 (5110 hom., cov: 32)
  • Exomes 𝑓: 0.29 (62877 hom.)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.00800
• Publications: 33 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=9.584427E-4).
• BP6: Variant 9-334337-A-G is Benign according to our data. Variant chr9-334337-A-G is described in ClinVar as Benign. ClinVar VariationId is 163174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.3 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.1238A>G	p.Asn413Ser	missense	Exon 11 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.1034A>G	p.Asn345Ser	missense	Exon 10 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.1034A>G	p.Asn345Ser	missense	Exon 10 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.1238A>G	p.Asn413Ser	missense	Exon 11 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.1034A>G	p.Asn345Ser	missense	Exon 10 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.1034A>G	p.Asn345Ser	missense	Exon 11 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38838 AN: 151950 Hom.: 5106 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.0328

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.303

Gnomad OTH AF: 0.271

GnomAD2 exomes AF: 0.245 AC: 61474 AN: 251170 AF XY: 0.252

Gnomad AFR exome AF: 0.219

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.333

Gnomad EAS exome AF: 0.0319

Gnomad FIN exome AF: 0.217

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.266

GnomAD4 exome AF: 0.287 AC: 419275 AN: 1461658 Hom.: 62877 Cov.: 36 AF XY: 0.287 AC XY: 208450 AN XY: 727122

African (AFR) AF: 0.215 AC: 7203 AN: 33476

American (AMR) AF: 0.158 AC: 7044 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 8684 AN: 26132

East Asian (EAS) AF: 0.0288 AC: 1142 AN: 39700

South Asian (SAS) AF: 0.258 AC: 22287 AN: 86252

European-Finnish (FIN) AF: 0.220 AC: 11767 AN: 53416

Middle Eastern (MID) AF: 0.327 AC: 1882 AN: 5762

European-Non Finnish (NFE) AF: 0.308 AC: 342489 AN: 1111808

Other (OTH) AF: 0.278 AC: 16777 AN: 60394

GnomAD4 genome AF: 0.255 AC: 38849 AN: 152068 Hom.: 5110 Cov.: 32 AF XY: 0.249 AC XY: 18505 AN XY: 74330

African (AFR) AF: 0.224 AC: 9307 AN: 41458

American (AMR) AF: 0.211 AC: 3231 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1130 AN: 3472

East Asian (EAS) AF: 0.0331 AC: 171 AN: 5164

South Asian (SAS) AF: 0.258 AC: 1244 AN: 4822

European-Finnish (FIN) AF: 0.208 AC: 2195 AN: 10576

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.303 AC: 20601 AN: 67976

Other (OTH) AF: 0.267 AC: 564 AN: 2110

Alfa AF: 0.285 Hom.: 21139

Bravo AF: 0.252

ESP6500AA AF: 0.229 AC: 1009

ESP6500EA AF: 0.309 AC: 2659

ExAC AF: 0.249 AC: 30196

Asia WGS AF: 0.135 AC: 472 AN: 3476

EpiCase AF: 0.308

EpiControl AF: 0.313

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Combined immunodeficiency due to DOCK8 deficiency (2)
-	-	2	not provided (3)
-	-	1	Not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.2
DANN	Benign	0.90
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.00096	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.33	N
PhyloP100		-0.0080
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.056
Sift	Benign	0.44	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.031
MPC		0.037
ClinPred		0.0034	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.023
gMVP		0.089
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs10970979; hg19: chr9-334337; COSMIC: COSV66634249;