rs377555406

chr4-3493265-G-Achr4-3493265-G-Cchr4-3493265-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_173660.5(DOK7):c.1279G>A(p.Gly427Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000745 in 1,611,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G427D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.285

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034209758).
• BP6: Variant 4-3493265-G-A is Benign according to our data. Variant chr4-3493265-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465672.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.1279G>A	p.Gly427Ser	missense_variant	7/7	ENST00000340083.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.1279G>A	p.Gly427Ser	missense_variant	7/7	1	NM_173660.5	P1
DOK7	ENST00000643608.1	c.847G>A	p.Gly283Ser	missense_variant	5/8
DOK7	ENST00000515886.5	c.349G>A	p.Gly117Ser	missense_variant	4/4	2
DOK7	ENST00000507039.5	c.*500G>A		3_prime_UTR_variant	7/7	2

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152210 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000552 AC: 13 AN: 235352 Hom.: 0 AF XY: 0.0000463 AC XY: 6 AN XY: 129466

Gnomad AFR exome AF: 0.000280

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000992

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000486

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000630 AC: 92 AN: 1459188 Hom.: 0 Cov.: 95 AF XY: 0.0000579 AC XY: 42 AN XY: 725828

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.0000996

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152328 Hom.: 0 Cov.: 34 AF XY: 0.000188 AC XY: 14 AN XY: 74480

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.000234

ExAC AF: 0.0000665 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 08, 2022

The c.1279G>A (p.G427S) alteration is located in exon 7 (coding exon 7) of the DOK7 gene. This alteration results from a G to A substitution at nucleotide position 1279, causing the glycine (G) at amino acid position 427 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 06, 2020

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	5.9
Dann	Benign	0.34
DEOGEN2	Benign	0.029	T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.39	T;T;T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.034	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.33	N;.;.
REVEL	Benign	0.044
Sift	Benign	0.40	T;.;.
Sift4G	Benign	1.0	T;.;.
Polyphen		0.0030	B;.;.
Vest4		0.036
MVP		0.46
MPC		0.0045
ClinPred		0.0086	T
GERP RS		1.9
Varity_R		0.033
gMVP		0.11

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: rs377555406; hg19: chr4-3494992; COSMIC: COSV60772347; COSMIC: COSV60772347;