9-214978-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2

The NM_203447.4(DOCK8):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000312 in 1,601,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

DOCK8
NM_203447.4 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.39

Variant links:

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 links:

DOCK8-AS1 (HGNC:26436): (DOCK8 antisense RNA 1)

DOCK8-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOCK8	NM_203447.4 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/48	ENST00000432829.7
DOCK8-AS1	NR_160804.1 linkuse as main transcript	n.773A>G		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOCK8	ENST00000432829.7 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/48	1	NM_203447.4		Q8NF50-1
DOCK8-AS1	ENST00000648587.1 linkuse as main transcript	n.764A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000229

AC:

AN:

217964

Hom.:

AF XY:

0.00

AC XY:

AN XY:

121740

show subpopulations

Gnomad AFR exome

AF:

0.000279

Gnomad AMR exome

AF:

0.0000305

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000276

AC:

AN:

1448950

Hom.:

Cov.:

110

AF XY:

0.0000291

AC XY:

AN XY:

720726

show subpopulations

Gnomad4 AFR exome

AF:

0.000157

Gnomad4 AMR exome

AF:

0.0000455

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000236

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000271

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000463

Hom.:

ExAC

AF:

0.0000173

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 14, 2022

Variant summary: DOCK8 c.2T>C (p.Met1?) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The next in-frame methionine is located in exon 3 at codon 69. The gnomAD GTEx v7 dataset shows that the first two exons of the longest transcript (NM_203447.3) are not expressed in several tissues including whole blood and spleen. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.3e-05 in 217964 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2T>C in individuals affected with Severe Combined Immunodeficiency and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014, and classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Combined immunodeficiency due to DOCK8 deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 2022

- -

Autosomal recessive hyper-IgE syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 15, 2022

ClinVar contains an entry for this variant (Variation ID: 1056064). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with DOCK8-related conditions. This variant is present in population databases (rs760902978, gnomAD 0.03%). This sequence change affects the initiator methionine of the DOCK8 mRNA. The next in-frame methionine is located at codon 69. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Benign

-0.24

Cadd

Uncertain

Dann

Uncertain

0.98

DEOGEN2

Benign

0.059

Eigen

Benign

0.044

Eigen_PC

Benign

0.080

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.37

M_CAP

Pathogenic

0.72

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

D;D;N

PROVEAN

Pathogenic

-7.0

REVEL

Benign

0.27

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.54

MutPred

0.21

Gain of MoRF binding (P = 0.0093);

MVP

0.19

MPC

0.32

ClinPred

0.17

GERP RS

4.9

Varity_R

0.81

gMVP

0.019

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over