rs191800156

Variant names:

• chr4-3463370-C-G
• rs191800156
• NM_173660.5:c.-6C>G

Your query was ambiguous. Multiple possible variants found:

• chr4-3463370-C-G
• chr4-3463370-C-A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_173660.5(DOK7):​c.-6C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 1,487,404 control chromosomes in the GnomAD database, including 527 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (23 hom., cov: 31)
  • Exomes 𝑓: 0.025 (504 hom.)
• Consequence: DOK7 NM_173660.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.69
• 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 4-3463370-C-G is Benign according to our data. Variant chr4-3463370-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 193509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0175 (2626/149922) while in subpopulation NFE AF = 0.0268 (1813/67748). AF 95% confidence interval is 0.0257. There are 23 homozygotes in GnomAd4. There are 1197 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 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.-6C>G		5_prime_UTR	Exon 1 of 7	NP_775931.3
	DOK7	NM_001301071.2		c.-6C>G		5_prime_UTR	Exon 1 of 10	NP_001288000.1	Q18PE1-3
	DOK7	NM_001363811.2		c.-6C>G		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.-6C>G		5_prime_UTR	Exon 1 of 7	ENSP00000344432.5	Q18PE1-1
	DOK7	ENST00000643608.1		c.-6C>G		5_prime_UTR	Exon 1 of 8	ENSP00000495701.1	A0A2R8Y701
	DOK7	ENST00000507039.5	TSL:2	c.-6C>G		5_prime_UTR	Exon 1 of 7	ENSP00000423614.1	Q18PE1-4

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2625 AN: 149822 Hom.: 23 Cov.: 31

Gnomad AFR AF: 0.00534

Gnomad AMI AF: 0.0254

Gnomad AMR AF: 0.0219

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00814

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.00987

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.0179

GnomAD2 exomes AF: 0.0149 AC: 1799 AN: 121120 AF XY: 0.0148

Gnomad AFR exome AF: 0.00288

Gnomad AMR exome AF: 0.00915

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0220

Gnomad OTH exome AF: 0.0187

GnomAD4 exome AF: 0.0253 AC: 33901 AN: 1337482 Hom.: 504 Cov.: 33 AF XY: 0.0250 AC XY: 16523 AN XY: 662094

African (AFR) AF: 0.00419 AC: 114 AN: 27188

American (AMR) AF: 0.0109 AC: 272 AN: 24988

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 351 AN: 21910

East Asian (EAS) AF: 0.0000306 AC: 1 AN: 32648

South Asian (SAS) AF: 0.00556 AC: 392 AN: 70496

European-Finnish (FIN) AF: 0.0124 AC: 448 AN: 36084

Middle Eastern (MID) AF: 0.0199 AC: 77 AN: 3862

European-Non Finnish (NFE) AF: 0.0292 AC: 31059 AN: 1065012

Other (OTH) AF: 0.0215 AC: 1187 AN: 55294

GnomAD4 genome AF: 0.0175 AC: 2626 AN: 149922 Hom.: 23 Cov.: 31 AF XY: 0.0164 AC XY: 1197 AN XY: 73052

African (AFR) AF: 0.00532 AC: 216 AN: 40586

American (AMR) AF: 0.0220 AC: 326 AN: 14830

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5032

South Asian (SAS) AF: 0.00815 AC: 39 AN: 4784

European-Finnish (FIN) AF: 0.0113 AC: 115 AN: 10196

Middle Eastern (MID) AF: 0.0106 AC: 3 AN: 284

European-Non Finnish (NFE) AF: 0.0268 AC: 1813 AN: 67748

Other (OTH) AF: 0.0177 AC: 37 AN: 2090

Alfa AF: 0.0195 Hom.: 5

Bravo AF: 0.0176

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	1	DOK7-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.96
PhyloP100		2.7
PromoterAI		0.020	Neutral
Mutation Taster		=298/2	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: rs191800156; hg19: chr4-3465097;