rs7854035

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_203447.4(DOCK8):​c.4491T>A​(p.Phe1497Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F1497F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DOCK8 NM_203447.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.330

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK8	NM_203447.4	c.4491T>A	p.Phe1497Leu	missense_variant	Exon 36 of 48	ENST00000432829.7	NP_982272.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK8	ENST00000432829.7	c.4491T>A	p.Phe1497Leu	missense_variant	Exon 36 of 48	1	NM_203447.4	ENSP00000394888.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 68

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.;.;T
Eigen	Benign	-0.063
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.095	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	-0.079	T
MutationAssessor	Uncertain	2.5	M;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.3	D;.;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0090	D;.;D;T
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.97	D;.;.;D
Vest4		0.91
MutPred		0.76		Loss of catalytic residue at F1497 (P = 0.061);.;.;.;
MVP		0.68
MPC		0.32
ClinPred		0.99	D
GERP RS		0.64
Varity_R		0.54
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

Other links and lift over

dbSNP: rs7854035; hg19: chr9-429719;