rs77051823

Variant names:

• chr4-3473663-G-A
• rs77051823
• NM_173660.5:c.331+27G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-3473663-G-A
• chr4-3473663-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_173660.5(DOK7):​c.331+27G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,519,254 control chromosomes in the GnomAD database, including 11,609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (957 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10652 hom.)
• Consequence: DOK7 NM_173660.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.95
• Publications: 5 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 4-3473663-G-A is Benign according to our data. Variant chr4-3473663-G-A is described in ClinVar as [Benign]. Clinvar id is 262873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOK7	NM_173660.5	c.331+27G>A		intron_variant	Intron 3 of 6	ENST00000340083.6	NP_775931.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOK7	ENST00000340083.6	c.331+27G>A		intron_variant	Intron 3 of 6	1	NM_173660.5	ENSP00000344432.5

Frequencies

GnomAD3 genomes AF: 0.0980 AC: 14913 AN: 152176 Hom.: 956 Cov.: 33

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0772

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.122

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.0990

GnomAD2 exomes AF: 0.135 AC: 18770 AN: 139488 AF XY: 0.132

Gnomad AFR exome AF: 0.0220

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.0762

Gnomad EAS exome AF: 0.236

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.123

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.119 AC: 162894 AN: 1366960 Hom.: 10652 Cov.: 33 AF XY: 0.119 AC XY: 79406 AN XY: 668394

African (AFR) AF: 0.0198 AC: 618 AN: 31172

American (AMR) AF: 0.181 AC: 6331 AN: 34970

Ashkenazi Jewish (ASJ) AF: 0.0722 AC: 1730 AN: 23948

East Asian (EAS) AF: 0.272 AC: 9602 AN: 35272

South Asian (SAS) AF: 0.104 AC: 7981 AN: 76416

European-Finnish (FIN) AF: 0.121 AC: 5691 AN: 46878

Middle Eastern (MID) AF: 0.106 AC: 418 AN: 3948

European-Non Finnish (NFE) AF: 0.117 AC: 124252 AN: 1057870

Other (OTH) AF: 0.111 AC: 6271 AN: 56486

GnomAD4 genome AF: 0.0979 AC: 14907 AN: 152294 Hom.: 957 Cov.: 33 AF XY: 0.101 AC XY: 7513 AN XY: 74472

African (AFR) AF: 0.0251 AC: 1044 AN: 41584

American (AMR) AF: 0.134 AC: 2055 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0772 AC: 268 AN: 3472

East Asian (EAS) AF: 0.227 AC: 1176 AN: 5174

South Asian (SAS) AF: 0.104 AC: 501 AN: 4826

European-Finnish (FIN) AF: 0.123 AC: 1309 AN: 10610

Middle Eastern (MID) AF: 0.128 AC: 37 AN: 290

European-Non Finnish (NFE) AF: 0.122 AC: 8282 AN: 68006

Other (OTH) AF: 0.0975 AC: 206 AN: 2112

Alfa AF: 0.111 Hom.: 193

Bravo AF: 0.0972

Asia WGS AF: 0.131 AC: 453 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.62
DANN	Benign	0.54
PhyloP100		-4.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs77051823; hg19: chr4-3475390; COSMIC: COSV60771511;