rs10972587

Variant names:

• chr9-368030-T-C
• rs10972587
• NM_203447.4:c.1692T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_203447.4(DOCK8):​c.1692T>C​(p.Tyr564Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 1,613,388 control chromosomes in the GnomAD database, including 6,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (2819 hom., cov: 32)
  • Exomes 𝑓: 0.043 (3296 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.590
• Publications: 9 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 9-368030-T-C is Benign according to our data. Variant chr9-368030-T-C is described in ClinVar as Benign. ClinVar VariationId is 137135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.355 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.1692T>C	p.Tyr564Tyr	synonymous	Exon 15 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.1488T>C	p.Tyr496Tyr	synonymous	Exon 14 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.1488T>C	p.Tyr496Tyr	synonymous	Exon 14 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.1692T>C	p.Tyr564Tyr	synonymous	Exon 15 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.1488T>C	p.Tyr496Tyr	synonymous	Exon 14 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.1488T>C	p.Tyr496Tyr	synonymous	Exon 15 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19242 AN: 152122 Hom.: 2808 Cov.: 32

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.0574

Gnomad ASJ AF: 0.0654

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0376

Gnomad OTH AF: 0.0999

GnomAD2 exomes AF: 0.0564 AC: 14170 AN: 251310 AF XY: 0.0497

Gnomad AFR exome AF: 0.366

Gnomad AMR exome AF: 0.0450

Gnomad ASJ exome AF: 0.0618

Gnomad EAS exome AF: 0.000816

Gnomad FIN exome AF: 0.0260

Gnomad NFE exome AF: 0.0382

Gnomad OTH exome AF: 0.0416

GnomAD4 exome AF: 0.0433 AC: 63218 AN: 1461148 Hom.: 3296 Cov.: 30 AF XY: 0.0418 AC XY: 30414 AN XY: 726942

African (AFR) AF: 0.364 AC: 12169 AN: 33430

American (AMR) AF: 0.0464 AC: 2074 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 1588 AN: 26128

East Asian (EAS) AF: 0.000831 AC: 33 AN: 39698

South Asian (SAS) AF: 0.0278 AC: 2394 AN: 86248

European-Finnish (FIN) AF: 0.0270 AC: 1444 AN: 53420

Middle Eastern (MID) AF: 0.0291 AC: 168 AN: 5764

European-Non Finnish (NFE) AF: 0.0362 AC: 40246 AN: 1111370

Other (OTH) AF: 0.0514 AC: 3102 AN: 60370

GnomAD4 genome AF: 0.127 AC: 19291 AN: 152240 Hom.: 2819 Cov.: 32 AF XY: 0.123 AC XY: 9154 AN XY: 74460

African (AFR) AF: 0.359 AC: 14911 AN: 41496

American (AMR) AF: 0.0574 AC: 878 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 227 AN: 3470

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.0269 AC: 130 AN: 4824

European-Finnish (FIN) AF: 0.0250 AC: 265 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0376 AC: 2558 AN: 68026

Other (OTH) AF: 0.0998 AC: 210 AN: 2104

Alfa AF: 0.0721 Hom.: 1769

Bravo AF: 0.139

Asia WGS AF: 0.0320 AC: 111 AN: 3478

EpiCase AF: 0.0365

EpiControl AF: 0.0324

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	3.1
DANN	Benign	0.52
PhyloP100		0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs10972587; hg19: chr9-368030;