rs146168804

Variant names:

• chr4-3463346-G-T
• rs146168804
• NM_173660.5:c.-30G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-3463346-G-T
• chr4-3463346-G-A
• chr4-3463346-G-C

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.-30G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,447,188 control chromosomes in the GnomAD database, including 8,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (678 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8138 hom.)
• Consequence: DOK7 NM_173660.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.61
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-3463346-G-T is Benign according to our data. Variant chr4-3463346-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 262861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

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.-30G>T		5_prime_UTR	Exon 1 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.-30G>T		5_prime_UTR	Exon 1 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.-30G>T		5_prime_UTR	Exon 1 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.-30G>T		5_prime_UTR	Exon 1 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.-30G>T		5_prime_UTR	Exon 1 of 8	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000507039.5	TSL:2	c.-30G>T		5_prime_UTR	Exon 1 of 7	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes AF: 0.0759 AC: 11521 AN: 151812 Hom.: 677 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0858

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.0280

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.0810

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.0993

Gnomad OTH AF: 0.0681

GnomAD2 exomes AF: 0.113 AC: 9379 AN: 83258 AF XY: 0.118

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.0322

Gnomad FIN exome AF: 0.0818

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.105 AC: 135896 AN: 1295270 Hom.: 8138 Cov.: 32 AF XY: 0.108 AC XY: 68873 AN XY: 637794

African (AFR) AF: 0.0151 AC: 398 AN: 26326

American (AMR) AF: 0.104 AC: 1909 AN: 18286

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2259 AN: 19894

East Asian (EAS) AF: 0.0213 AC: 674 AN: 31666

South Asian (SAS) AF: 0.231 AC: 14641 AN: 63248

European-Finnish (FIN) AF: 0.0742 AC: 2545 AN: 34302

Middle Eastern (MID) AF: 0.0728 AC: 270 AN: 3708

European-Non Finnish (NFE) AF: 0.103 AC: 107773 AN: 1044314

Other (OTH) AF: 0.101 AC: 5427 AN: 53526

GnomAD4 genome AF: 0.0759 AC: 11527 AN: 151918 Hom.: 678 Cov.: 32 AF XY: 0.0784 AC XY: 5820 AN XY: 74246

African (AFR) AF: 0.0175 AC: 727 AN: 41498

American (AMR) AF: 0.0863 AC: 1319 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 444 AN: 3468

East Asian (EAS) AF: 0.0283 AC: 145 AN: 5118

South Asian (SAS) AF: 0.227 AC: 1096 AN: 4820

European-Finnish (FIN) AF: 0.0810 AC: 854 AN: 10548

Middle Eastern (MID) AF: 0.0856 AC: 25 AN: 292

European-Non Finnish (NFE) AF: 0.0994 AC: 6744 AN: 67874

Other (OTH) AF: 0.0670 AC: 141 AN: 2106

Alfa AF: 0.0438 Hom.: 34

Bravo AF: 0.0684

Asia WGS AF: 0.109 AC: 369 AN: 3368

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	16
DANN	Benign	0.83
PhyloP100		1.6
PromoterAI		0.00050	Neutral
Mutation Taster		=299/1	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: rs146168804; hg19: chr4-3465073;