chr4-3463407-T-C

Position:

• chr4-3463407-T-C

Variant summary

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

The NM_173660.5(DOK7):​c.32T>C​(p.Val11Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000423 in 1,370,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V11L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.785

Genes affected

DOK7 (HGNC:26594): (docking protein 7) The protein encoded by this gene is essential for neuromuscular synaptogenesis. The protein functions in aneural activation of muscle-specific receptor kinase, which is required for postsynaptic differentiation, and in the subsequent clustering of the acetylcholine receptor in myotubes. This protein can also induce autophosphorylation of muscle-specific receptor kinase. Mutations in this gene are a cause of familial limb-girdle myasthenia autosomal recessive, which is also known as congenital myasthenic syndrome type 1B. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

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=0.12990925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.32T>C	p.Val11Ala	missense_variant	1/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.32T>C	p.Val11Ala	missense_variant	1/7	1	NM_173660.5	P1

Frequencies

GnomAD3 genomes AF: 0.000231 AC: 30 AN: 129954 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000765

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000166

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: 0.00

Gnomad OTH AF: 0.00107

GnomAD4 exome AF: 0.0000218 AC: 27 AN: 1240230 Hom.: 0 Cov.: 35 AF XY: 0.0000212 AC XY: 13 AN XY: 612100

Gnomad4 AFR exome AF: 0.000759

Gnomad4 AMR exome AF: 0.0000902

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000422

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000101

GnomAD4 genome AF: 0.000238 AC: 31 AN: 129998 Hom.: 0 Cov.: 30 AF XY: 0.000177 AC XY: 11 AN XY: 62070

Gnomad4 AFR AF: 0.000793

Gnomad4 AMR AF: 0.000166

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00106

Alfa AF: 0.000337 Hom.: 0

Bravo AF: 0.000264

ESP6500AA AF: 0.000296 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000272 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

The c.32T>C (p.V11A) alteration is located in exon 1 (coding exon 1) of the DOK7 gene. This alteration results from a T to C substitution at nucleotide position 32, causing the valine (V) at amino acid position 11 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2022

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 11 of the DOK7 protein (p.Val11Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of DOK7-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 1005955). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.15	.;T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.3	L;L;.
MutationTaster	Benign	0.93	N;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.8	N;N;.
REVEL	Benign	0.18
Sift	Benign	0.10	T;T;.
Sift4G	Benign	0.22	T;T;.
Polyphen		0.0040	.;B;.
Vest4		0.25
MVP		0.68
MPC		0.0048
ClinPred		0.027	T
GERP RS		2.3
Varity_R		0.14
gMVP		0.42

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: rs375168516; hg19: chr4-3465134;