rs7854035

Variant names:

• chr9-429719-T-C
• rs7854035
• NM_203447.4:c.4491T>C

Your query was ambiguous. Multiple possible variants found:

• chr9-429719-T-C
• chr9-429719-T-A
• chr9-429719-T-G

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.4491T>C​(p.Phe1497Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 1,614,220 control chromosomes in the GnomAD database, including 800,807 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75764 hom., cov: 33)
  • Exomes 𝑓: 1.0 (725043 hom.)
• Consequence: DOCK8 NM_203447.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.330
• Publications: 17 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=-0.54).
• BP6: Variant 9-429719-T-C is Benign according to our data. Variant chr9-429719-T-C is described in ClinVar as Benign. ClinVar VariationId is 178770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.33 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.991 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.4491T>C	p.Phe1497Phe	synonymous	Exon 36 of 48	NP_982272.2	Q8NF50-1
	DOCK8	NM_001193536.2		c.4287T>C	p.Phe1429Phe	synonymous	Exon 35 of 47	NP_001180465.1	Q8NF50-3
	DOCK8	NM_001190458.2		c.4191T>C	p.Phe1397Phe	synonymous	Exon 34 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.4491T>C	p.Phe1497Phe	synonymous	Exon 36 of 48	ENSP00000394888.3	Q8NF50-1
	DOCK8	ENST00000469391.5	TSL:1	c.4191T>C	p.Phe1397Phe	synonymous	Exon 34 of 46	ENSP00000419438.1	Q8NF50-4
	DOCK8	ENST00000382329.2	TSL:1	c.4191T>C	p.Phe1397Phe	synonymous	Exon 35 of 46	ENSP00000371766.2	A2A369

Frequencies

GnomAD3 genomes AF: 0.997 AC: 151815 AN: 152224 Hom.: 75704 Cov.: 33

Gnomad AFR AF: 0.999

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.996

Gnomad OTH AF: 0.993

GnomAD2 exomes AF: 0.998 AC: 250893 AN: 251468 AF XY: 0.998

Gnomad AFR exome AF: 0.999

Gnomad AMR exome AF: 0.996

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.997

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.996 AC: 1455972 AN: 1461878 Hom.: 725043 Cov.: 68 AF XY: 0.996 AC XY: 724447 AN XY: 727244

African (AFR) AF: 0.999 AC: 33458 AN: 33480

American (AMR) AF: 0.996 AC: 44541 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26127 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39694 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86232 AN: 86258

European-Finnish (FIN) AF: 1.00 AC: 53405 AN: 53418

Middle Eastern (MID) AF: 1.00 AC: 5762 AN: 5762

European-Non Finnish (NFE) AF: 0.995 AC: 1106570 AN: 1112006

Other (OTH) AF: 0.997 AC: 60183 AN: 60394

GnomAD4 genome AF: 0.997 AC: 151934 AN: 152342 Hom.: 75764 Cov.: 33 AF XY: 0.998 AC XY: 74312 AN XY: 74490

African (AFR) AF: 0.999 AC: 41536 AN: 41572

American (AMR) AF: 0.995 AC: 15235 AN: 15308

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3471 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5172 AN: 5172

South Asian (SAS) AF: 1.00 AC: 4826 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10626 AN: 10626

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.996 AC: 67761 AN: 68042

Other (OTH) AF: 0.993 AC: 2102 AN: 2116

Alfa AF: 0.997 Hom.: 27106

Bravo AF: 0.997

Asia WGS AF: 1.00 AC: 3478 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	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	-0.54
CADD	Benign	1.8
DANN	Benign	0.64
PhyloP100		0.33
Mutation Taster		=26/74	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: rs7854035; hg19: chr9-429719; COSMIC: COSV108223946; COSMIC: COSV108223946;