20-54643458-C-T

Variant summary

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

The NM_018431.5(DOK5):c.736C>T(p.Leu246Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,076 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DOK5 NM_018431.5 missense, splice_region
• Scores: Splicing: ADA: 0.9963
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.32

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK5	NM_018431.5	c.736C>T	p.Leu246Phe	missense_variant, splice_region_variant	7/8	ENST00000262593.10
DOK5	NM_177959.3	c.412C>T	p.Leu138Phe	missense_variant, splice_region_variant	7/8
DOK5	XM_024451946.2	c.700C>T	p.Leu234Phe	missense_variant, splice_region_variant	7/8
DOK5	XM_011528904.2	c.412C>T	p.Leu138Phe	missense_variant, splice_region_variant	7/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK5	ENST00000262593.10	c.736C>T	p.Leu246Phe	missense_variant, splice_region_variant	7/8	1	NM_018431.5	P1
DOK5	ENST00000395939.5	c.412C>T	p.Leu138Phe	missense_variant, splice_region_variant	7/8	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461076 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 726850

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000356 Hom.: 0

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Sep 29, 2022

The c.736C>T (p.L246F) alteration is located in exon 7 (coding exon 7) of the DOK5 gene. This alteration results from a C to T substitution at nucleotide position 736, causing the leucine (L) at amino acid position 246 to be replaced by a phenylalanine (F). 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	0.092
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.087	T;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.98	D;D
Vest4		0.38
MVP		0.97
MPC		0.48
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.27
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.010		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: rs1469763130; hg19: chr20-53259997;