rs375468951

Positions:

• chr4-3476337-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_173660.5(DOK7):​c.332-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000072 in 1,610,488 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00034 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000044 (1 hom.)
• Consequence: DOK7 NM_173660.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002524
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.160

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]

LOC105374355 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 4-3476337-C-T is Benign according to our data. Variant chr4-3476337-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 534128.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOK7	NM_173660.5	c.332-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000340083.6
LOC105374355	XR_007057994.1	n.829G>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOK7	ENST00000340083.6	c.332-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_173660.5	P1

Frequencies

GnomAD3 genomes AF: 0.000345 AC: 52 AN: 150680 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00115

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.000101 AC: 25 AN: 246992 Hom.: 1 AF XY: 0.0000967 AC XY: 13 AN XY: 134442

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1459698 Hom.: 1 Cov.: 40 AF XY: 0.0000344 AC XY: 25 AN XY: 726266

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000345 AC: 52 AN: 150790 Hom.: 1 Cov.: 31 AF XY: 0.000353 AC XY: 26 AN XY: 73660

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.000133

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000388 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.6
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.030
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

Publications

LitVar

Other links and lift over

dbSNP: rs375468951; hg19: chr4-3478064;