4-3489777-G-T

Variant names:

• chr4-3489777-G-T
• rs59932476
• NM_173660.5:c.753G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_173660.5(DOK7):​c.753G>T​(p.Ala251Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,420,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A251A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DOK7 NM_173660.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: -2.31
• Publications: 10 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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.108039826).
• BP6: Variant 4-3489777-G-T is Benign according to our data. Variant chr4-3489777-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2934861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.32 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	NM_173660.5	MANE Select	c.753G>T	p.Ala251Ala	synonymous	Exon 6 of 7	NP_775931.3
	DOK7	NM_001256896.2		c.-178G>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 4	NP_001243825.1
	DOK7	NM_001164673.2		c.742G>T	p.Gly248Trp	missense	Exon 6 of 7	NP_001158145.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOK7	ENST00000340083.6	TSL:1 MANE Select	c.753G>T	p.Ala251Ala	synonymous	Exon 6 of 7	ENSP00000344432.5
	DOK7	ENST00000513995.1	TSL:1	n.411G>T		non_coding_transcript_exon	Exon 2 of 3
	DOK7	ENST00000515886.5	TSL:2	c.-178G>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 4	ENSP00000492194.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183538 AF XY: 0.0000102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000132

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1420692 Hom.: 0 Cov.: 32 AF XY: 0.00000285 AC XY: 2 AN XY: 702746

African (AFR) AF: 0.00 AC: 0 AN: 32714

American (AMR) AF: 0.00 AC: 0 AN: 39220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25352

East Asian (EAS) AF: 0.00 AC: 0 AN: 37534

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1090924

Other (OTH) AF: 0.00 AC: 0 AN: 58804

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DOK7-related disorder Uncertain:1

May 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DOK7 c.742G>T variant is predicted to result in the amino acid substitution p.Gly248Trp. Of note, in the primary transcript listed in the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk/ac/index.php; NM_173660), this variant does not result in an amino acid change (c.753G>T, p.=). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0041% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Inborn genetic diseases Benign:1

Aug 27, 2025

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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

Jan 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	0.062
DANN	Benign	0.54
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0081	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	-0.022	T
PhyloP100		-2.3
PROVEAN	Benign	0.25	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Vest4		0.33
MVP		0.48
ClinPred		0.034	T
GERP RS		-1.9
Mutation Taster		=99/1	polymorphism

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: rs59932476; hg19: chr4-3491504;