5-177504377-G-A

Variant summary

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

The NM_001308236.3(DOK3):c.929C>T(p.Pro310Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,568,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: DOK3 NM_001308236.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

Genes affected

DOK3 (HGNC:24583): (docking protein 3) Predicted to be involved in Ras protein signal transduction and transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to be located in ficolin-1-rich granule membrane and plasma membrane. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.081258446).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK3	NM_001308236.3	c.929C>T	p.Pro310Leu	missense_variant	6/6	ENST00000510898.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK3	ENST00000510898.7	c.929C>T	p.Pro310Leu	missense_variant	6/6	3	NM_001308236.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000333 AC: 7 AN: 210280 Hom.: 0 AF XY: 0.0000177 AC XY: 2 AN XY: 113096

Gnomad AFR exome AF: 0.0000670

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000162

Gnomad EAS exome AF: 0.000172

Gnomad SAS exome AF: 0.0000445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000103

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000170 AC: 24 AN: 1415804 Hom.: 0 Cov.: 30 AF XY: 0.0000186 AC XY: 13 AN XY: 698932

Gnomad4 AFR exome AF: 0.0000932

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000876

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000110

Gnomad4 OTH exome AF: 0.0000344

GnomAD4 genome AF: 0.0000656 AC: 10 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74486

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Oct 12, 2021

The c.1097C>T (p.P366L) alteration is located in exon 6 (coding exon 6) of the DOK3 gene. This alteration results from a C to T substitution at nucleotide position 1097, causing the proline (P) at amino acid position 366 to be replaced by a leucine (L). 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	0.25
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.071	T;T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.27	N
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.081	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.71	T
Polyphen		0.40	.;B;.
Vest4		0.33, 0.33
MVP		0.24
MPC		0.28
ClinPred		0.15	T
GERP RS		3.0
Varity_R		0.12
gMVP		0.32

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

Other links and lift over

dbSNP: rs367712454; hg19: chr5-176931378;