9-441952-G-A

Variant names:

• chr9-441952-G-A
• rs1887957
• NM_203447.4:c.5433G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):​c.5433G>A​(p.Glu1811Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.813 in 1,613,816 control chromosomes in the GnomAD database, including 536,424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (45203 hom., cov: 31)
  • Exomes 𝑓: 0.82 (491221 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 0.269
• Publications: 26 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 9-441952-G-A is Benign according to our data. Variant chr9-441952-G-A is described in ClinVar as Benign. ClinVar VariationId is 178771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.269 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.972 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.5433G>A	p.Glu1811Glu	synonymous	Exon 42 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.5229G>A	p.Glu1743Glu	synonymous	Exon 41 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.5133G>A	p.Glu1711Glu	synonymous	Exon 40 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.5433G>A	p.Glu1811Glu	synonymous	Exon 42 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.5133G>A	p.Glu1711Glu	synonymous	Exon 40 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.5133G>A	p.Glu1711Glu	synonymous	Exon 41 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.763 AC: 116031 AN: 151978 Hom.: 45172 Cov.: 31

Gnomad AFR AF: 0.593

Gnomad AMI AF: 0.740

Gnomad AMR AF: 0.848

Gnomad ASJ AF: 0.784

Gnomad EAS AF: 0.994

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.819

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.816

Gnomad OTH AF: 0.771

GnomAD2 exomes AF: 0.825 AC: 207418 AN: 251418 AF XY: 0.826

Gnomad AFR exome AF: 0.591

Gnomad AMR exome AF: 0.882

Gnomad ASJ exome AF: 0.763

Gnomad EAS exome AF: 0.996

Gnomad FIN exome AF: 0.831

Gnomad NFE exome AF: 0.820

Gnomad OTH exome AF: 0.824

GnomAD4 exome AF: 0.818 AC: 1196128 AN: 1461720 Hom.: 491221 Cov.: 55 AF XY: 0.819 AC XY: 595315 AN XY: 727162

African (AFR) AF: 0.588 AC: 19665 AN: 33472

American (AMR) AF: 0.878 AC: 39290 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.765 AC: 19996 AN: 26128

East Asian (EAS) AF: 0.998 AC: 39587 AN: 39686

South Asian (SAS) AF: 0.818 AC: 70518 AN: 86250

European-Finnish (FIN) AF: 0.830 AC: 44330 AN: 53398

Middle Eastern (MID) AF: 0.785 AC: 4523 AN: 5764

European-Non Finnish (NFE) AF: 0.818 AC: 909191 AN: 1111908

Other (OTH) AF: 0.812 AC: 49028 AN: 60390

GnomAD4 genome AF: 0.763 AC: 116118 AN: 152096 Hom.: 45203 Cov.: 31 AF XY: 0.768 AC XY: 57059 AN XY: 74342

African (AFR) AF: 0.594 AC: 24619 AN: 41466

American (AMR) AF: 0.848 AC: 12963 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.784 AC: 2722 AN: 3472

East Asian (EAS) AF: 0.994 AC: 5142 AN: 5172

South Asian (SAS) AF: 0.822 AC: 3966 AN: 4824

European-Finnish (FIN) AF: 0.819 AC: 8656 AN: 10574

Middle Eastern (MID) AF: 0.850 AC: 250 AN: 294

European-Non Finnish (NFE) AF: 0.816 AC: 55498 AN: 67990

Other (OTH) AF: 0.773 AC: 1627 AN: 2106

Alfa AF: 0.792 Hom.: 31958

Bravo AF: 0.758

Asia WGS AF: 0.899 AC: 3127 AN: 3478

EpiCase AF: 0.814

EpiControl AF: 0.820

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.8
DANN	Benign	0.53
PhyloP100		0.27
Mutation Taster		=100/0	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: rs1887957; hg19: chr9-441952; COSMIC: COSV66622581;