rs118203994

Variant names:

• chr4-3485545-G-C
• rs118203994
• NM_173660.5:c.539G>C

Your query was ambiguous. Multiple possible variants found:

• chr4-3485545-G-C
• chr4-3485545-G-A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_173660.5(DOK7):​c.539G>C​(p.Gly180Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,449,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G180G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DOK7 NM_173660.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.34
• Publications: 4 publications found

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]

DOK7 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 10

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• fetal akinesia deformation sequence 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 4-3485545-G-C is Pathogenic according to our data. Variant chr4-3485545-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173660.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.539G>C	p.Gly180Ala	missense	Exon 5 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.539G>C	p.Gly180Ala	missense	Exon 5 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.107G>C	p.Gly36Ala	missense	Exon 3 of 8	NP_001350740.1	A0A2R8Y701

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.539G>C	p.Gly180Ala	missense	Exon 5 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000513995.1	TSL:1	n.197G>C		non_coding_transcript_exon	Exon 1 of 3
	DOK7	ENST00000643608.1		c.107G>C	p.Gly36Ala	missense	Exon 3 of 8	ENSP00000495701.1	A0A2R8Y701

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000123 AC: 3 AN: 243482 AF XY: 0.0000152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000172

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1449886 Hom.: 0 Cov.: 33 AF XY: 0.00000416 AC XY: 3 AN XY: 720698

African (AFR) AF: 0.00 AC: 0 AN: 32952

American (AMR) AF: 0.00 AC: 0 AN: 43972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.000129 AC: 5 AN: 38772

South Asian (SAS) AF: 0.00 AC: 0 AN: 84686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105510

Other (OTH) AF: 0.00 AC: 0 AN: 59864

GnomAD4 genome Cov.: 34

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital myasthenic syndrome (1)
1	-	-	Congenital myasthenic syndrome 10 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	26
DANN	Benign	0.93
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.89	D
PhyloP100		7.3
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.010	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.80	P
Vest4		0.96
MutPred		0.87		Loss of loop (P = 0.0073)
MVP		0.93
MPC		0.019
ClinPred		0.95	D
GERP RS		3.8
Varity_R		0.76
gMVP		0.88
Mutation Taster		=8/92	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs118203994; hg19: chr4-3487272;