4-3493455-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_173660.5(DOK7):c.1469C>T(p.Ser490Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,609,980 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S490W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 35)
  • Exomes 𝑓: 0.0019 (25 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.49

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022628307).
• BP6: Variant 4-3493455-C-T is Benign according to our data. Variant chr4-3493455-C-T is described in ClinVar as [Benign]. Clinvar id is 262868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00258 (393/152362) while in subpopulation EAS AF= 0.0284 (147/5180). AF 95% confidence interval is 0.0246. There are 4 homozygotes in gnomad4. There are 210 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.1469C>T	p.Ser490Leu	missense_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.1469C>T	p.Ser490Leu	missense_variant	7/7	1	NM_173660.5	P1
DOK7	ENST00000643608.1	c.1037C>T	p.Ser346Leu	missense_variant	5/8
DOK7	ENST00000515886.5	c.539C>T	p.Ser180Leu	missense_variant	4/4	2
DOK7	ENST00000507039.5	c.*690C>T		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.00257 AC: 392 AN: 152244 Hom.: 4 Cov.: 35

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0285

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00528 AC: 1242 AN: 235078 Hom.: 11 AF XY: 0.00473 AC XY: 612 AN XY: 129510

Gnomad AFR exome AF: 0.000864

Gnomad AMR exome AF: 0.00470

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.0363

Gnomad SAS exome AF: 0.000635

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.000970

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00185 AC: 2699 AN: 1457618 Hom.: 25 Cov.: 88 AF XY: 0.00176 AC XY: 1275 AN XY: 724860

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00438

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.0270

Gnomad4 SAS exome AF: 0.000816

Gnomad4 FIN exome AF: 0.0144

Gnomad4 NFE exome AF: 0.000420

Gnomad4 OTH exome AF: 0.00233

GnomAD4 genome AF: 0.00258 AC: 393 AN: 152362 Hom.: 4 Cov.: 35 AF XY: 0.00282 AC XY: 210 AN XY: 74504

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0284

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00214 Hom.: 2

Bravo AF: 0.00240

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000499 AC: 4

ExAC AF: 0.00474 AC: 569

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Fetal akinesia deformation sequence 3 Benign:1

Benign, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Sep 26, 2018

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	22
Dann	Benign	0.94
DEOGEN2	Benign	0.10	T;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.74	T;T;T
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.1	N;.;.
REVEL	Benign	0.049
Sift	Benign	0.22	T;.;.
Sift4G	Benign	0.096	T;.;.
Polyphen		0.0010	B;.;.
Vest4		0.18
MVP		0.54
MPC		0.0048
ClinPred		0.0041	T
GERP RS		1.0
Varity_R		0.064
gMVP		0.13

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: rs77513082; hg19: chr4-3495182;