NM_001367561.1:c.3472-5A>G

Variant names:

• chr1-62535637-T-C
• rs76660788
• NM_001367561.1:c.3472-5A>G

Variant summary

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

The NM_001367561.1(DOCK7):​c.3472-5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,612,494 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (73 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (82 hom.)
• Consequence: DOCK7 NM_001367561.1 splice_region, intron
• Scores: Splicing: ADA: 0.0002429
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0330
• Publications: 1 publications found

Genes affected

DOCK7 (HGNC:19190): (dedicator of cytokinesis 7) The protein encoded by this gene is a guanine nucleotide exchange factor (GEF) that plays a role in axon formation and neuronal polarization. The encoded protein displays GEF activity toward RAC1 and RAC3 Rho small GTPases but not toward CDC42. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

DOCK7 Gene-Disease associations (from GenCC):

• genetic developmental and epileptic encephalopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 23

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-62535637-T-C is Benign according to our data. Variant chr1-62535637-T-C is described in ClinVar as Benign. ClinVar VariationId is 475137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367561.1. 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
	DOCK7	NM_001367561.1	MANE Select	c.3472-5A>G		splice_region intron	N/A	NP_001354490.1
	DOCK7	NM_001330614.2		c.3472-5A>G		splice_region intron	N/A	NP_001317543.1
	DOCK7	NM_001271999.2		c.3472-5A>G		splice_region intron	N/A	NP_001258928.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK7	ENST00000635253.2	TSL:5 MANE Select	c.3472-5A>G		splice_region intron	N/A	ENSP00000489124.1
	DOCK7	ENST00000454575.6	TSL:1	c.3472-5A>G		splice_region intron	N/A	ENSP00000413583.2
	DOCK7	ENST00000912940.1		c.3472-5A>G		splice_region intron	N/A	ENSP00000582999.1

Frequencies

GnomAD3 genomes AF: 0.0171 AC: 2601 AN: 152174 Hom.: 73 Cov.: 33

Gnomad AFR AF: 0.0592

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.00481 AC: 1200 AN: 249352 AF XY: 0.00368

Gnomad AFR exome AF: 0.0614

Gnomad AMR exome AF: 0.00410

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000213

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00198 AC: 2889 AN: 1460202 Hom.: 82 Cov.: 31 AF XY: 0.00171 AC XY: 1243 AN XY: 726376

African (AFR) AF: 0.0653 AC: 2186 AN: 33460

American (AMR) AF: 0.00431 AC: 192 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39600

South Asian (SAS) AF: 0.00107 AC: 92 AN: 85932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5760

European-Non Finnish (NFE) AF: 0.000120 AC: 133 AN: 1111198

Other (OTH) AF: 0.00458 AC: 276 AN: 60322

GnomAD4 genome AF: 0.0172 AC: 2614 AN: 152292 Hom.: 73 Cov.: 33 AF XY: 0.0168 AC XY: 1251 AN XY: 74474

African (AFR) AF: 0.0593 AC: 2465 AN: 41568

American (AMR) AF: 0.00608 AC: 93 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68016

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.00967 Hom.: 32

Bravo AF: 0.0200

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000383

EpiControl AF: 0.000357

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Developmental and epileptic encephalopathy, 23 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	15
DANN	Benign	0.50
PhyloP100		0.033
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.014
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.37		Position offset: 47

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs76660788; hg19: chr1-63001308;