20-54643532-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018431.5(DOK5):c.810G>C(p.Gln270His) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DOK5 NM_018431.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34

Genes affected

DOK5 (HGNC:16173): (docking protein 5) The protein encoded by this gene is a member of the DOK family of membrane proteins, which are adapter proteins involved in signal transduction. The encoded protein interacts with phosphorylated receptor tyrosine kinases to mediate neurite outgrowth and activation of the MAP kinase pathway. Unlike other DOK family proteins, this protein does not interact with RASGAP. This protein is up-regulated in patients with systemic sclerosis and is associated with fibrosis induced by insulin-like growth factor binding protein 5. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.111546755).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK5	NM_018431.5	c.810G>C	p.Gln270His	missense_variant	7/8	ENST00000262593.10
DOK5	NM_177959.3	c.486G>C	p.Gln162His	missense_variant	7/8
DOK5	XM_024451946.2	c.774G>C	p.Gln258His	missense_variant	7/8
DOK5	XM_011528904.2	c.486G>C	p.Gln162His	missense_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK5	ENST00000262593.10	c.810G>C	p.Gln270His	missense_variant	7/8	1	NM_018431.5	P1
DOK5	ENST00000395939.5	c.486G>C	p.Gln162His	missense_variant	7/8	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.810G>C (p.Q270H) alteration is located in exon 7 (coding exon 7) of the DOK5 gene. This alteration results from a G to C substitution at nucleotide position 810, causing the glutamine (Q) at amino acid position 270 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	13
Dann	Benign	0.19
DEOGEN2	Benign	0.019	T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.27	N;.
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	1.3	N;N
REVEL	Benign	0.23
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.31
MutPred		0.59		Loss of MoRF binding (P = 0.0924);.;
MVP		0.78
MPC		0.37
ClinPred		0.098	T
GERP RS		2.4
Varity_R		0.042
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-53260071;