4-3463458-G-C

Variant names:

• chr4-3463458-G-C
• rs767030857
• NM_173660.5:c.54+29G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_173660.5(DOK7):​c.54+29G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,424,582 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00047 (2 hom., cov: 26)
  • Exomes 𝑓: 0.00031 (2 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.229
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, PanelApp Australia
• fetal akinesia deformation sequence 3

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 4-3463458-G-C is Benign according to our data. Variant chr4-3463458-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1597005.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.54+29G>C		intron	N/A	NP_775931.3
	DOK7	NM_001301071.2		c.54+29G>C		intron	N/A	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.54+29G>C		intron	N/A	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.54+29G>C		intron	N/A	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.54+29G>C		intron	N/A	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000507039.5	TSL:2	c.54+29G>C		intron	N/A	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes AF: 0.000465 AC: 70 AN: 150412 Hom.: 2 Cov.: 26

Gnomad AFR AF: 0.000292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00326

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000313

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000212 AC: 11 AN: 52006 AF XY: 0.000304

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000305

Gnomad FIN exome AF: 0.00214

Gnomad NFE exome AF: 0.000149

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000315 AC: 401 AN: 1274082 Hom.: 2 Cov.: 47 AF XY: 0.000315 AC XY: 197 AN XY: 625986

African (AFR) AF: 0.000357 AC: 9 AN: 25176

American (AMR) AF: 0.000151 AC: 3 AN: 19892

Ashkenazi Jewish (ASJ) AF: 0.0000996 AC: 2 AN: 20086

East Asian (EAS) AF: 0.0000345 AC: 1 AN: 29026

South Asian (SAS) AF: 0.0000622 AC: 4 AN: 64296

European-Finnish (FIN) AF: 0.00643 AC: 205 AN: 31866

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3696

European-Non Finnish (NFE) AF: 0.000152 AC: 156 AN: 1027154

Other (OTH) AF: 0.000397 AC: 21 AN: 52890

GnomAD4 genome AF: 0.000465 AC: 70 AN: 150500 Hom.: 2 Cov.: 26 AF XY: 0.000653 AC XY: 48 AN XY: 73474

African (AFR) AF: 0.000292 AC: 12 AN: 41146

American (AMR) AF: 0.000132 AC: 2 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5068

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4778

European-Finnish (FIN) AF: 0.00326 AC: 34 AN: 10436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000313 AC: 21 AN: 67138

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000939 Hom.: 1

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Fetal akinesia deformation sequence 1;C1850792:Congenital myasthenic syndrome 10 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		0.23
PromoterAI		-0.025	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs767030857; hg19: chr4-3465185;