9-414824-C-T

Variant names:

• chr9-414824-C-T
• rs13285348
• NM_203447.4:c.3573C>T
• DOCK8 p.Ser1191Ser

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_203447.4(DOCK8):​c.3573C>T​(p.Ser1191Ser) variant causes a synonymous change. The variant allele was found at a frequency of 0.00937 in 1,614,196 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (6 hom., cov: 33)
  • Exomes 𝑓: 0.0097 (101 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 3.86
• Publications: 4 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.19).
• BP6: Variant 9-414824-C-T is Benign according to our data. Variant chr9-414824-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 163175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00652 (993/152314) while in subpopulation NFE AF = 0.0101 (690/68026). AF 95% confidence interval is 0.00952. There are 6 homozygotes in GnomAd4. There are 437 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.3573C>T	p.Ser1191Ser	synonymous	Exon 29 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.3369C>T	p.Ser1123Ser	synonymous	Exon 28 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.3273C>T	p.Ser1091Ser	synonymous	Exon 27 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.3573C>T	p.Ser1191Ser	synonymous	Exon 29 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.3273C>T	p.Ser1091Ser	synonymous	Exon 27 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.3273C>T	p.Ser1091Ser	synonymous	Exon 28 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.00652 AC: 993 AN: 152196 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00224

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.00746

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00570 AC: 1434 AN: 251466 AF XY: 0.00553

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.00515

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00106

Gnomad NFE exome AF: 0.00981

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00967 AC: 14133 AN: 1461882 Hom.: 101 Cov.: 32 AF XY: 0.00925 AC XY: 6726 AN XY: 727244

African (AFR) AF: 0.00206 AC: 69 AN: 33480

American (AMR) AF: 0.00539 AC: 241 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

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

South Asian (SAS) AF: 0.00141 AC: 122 AN: 86256

European-Finnish (FIN) AF: 0.00129 AC: 69 AN: 53420

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0117 AC: 13000 AN: 1112002

Other (OTH) AF: 0.0101 AC: 613 AN: 60396

GnomAD4 genome AF: 0.00652 AC: 993 AN: 152314 Hom.: 6 Cov.: 33 AF XY: 0.00587 AC XY: 437 AN XY: 74472

African (AFR) AF: 0.00224 AC: 93 AN: 41566

American (AMR) AF: 0.00745 AC: 114 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4820

European-Finnish (FIN) AF: 0.000942 AC: 10 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0101 AC: 690 AN: 68026

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.00764 Hom.: 5

Bravo AF: 0.00760

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0104

EpiControl AF: 0.00984

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Benign	8.5
DANN	Benign	0.76
PhyloP100		3.9
Mutation Taster		=71/29	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: rs13285348;

hg19: chr9-414824;