1-62625414-TA-TAA

Variant names:

• chr1-62625414-T-TA
• rs541344421
• NM_001367561.1:c.1283-14dupT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The ENST00000635253.2(DOCK7):​c.1283-14_1283-13insT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000853 in 1,511,166 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (0 hom.)
• Consequence: DOCK7 ENST00000635253.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.26
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 1-62625414-T-TA is Benign according to our data. Variant chr1-62625414-T-TA is described in ClinVar as Benign. ClinVar VariationId is 1604867.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000635253.2. 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
	DOCK7	NM_001367561.1	MANE Select	c.1283-14dupT		intron	N/A	NP_001354490.1
	DOCK7	NM_001330614.2		c.1283-14dupT		intron	N/A	NP_001317543.1
	DOCK7	NM_001271999.2		c.1283-14dupT		intron	N/A	NP_001258928.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK7	ENST00000635253.2	TSL:5 MANE Select	c.1283-14_1283-13insT		intron	N/A	ENSP00000489124.1
	DOCK7	ENST00000454575.6	TSL:1	c.1283-14_1283-13insT		intron	N/A	ENSP00000413583.2
	DOCK7	ENST00000251157.10	TSL:5	c.1283-14_1283-13insT		intron	N/A	ENSP00000251157.6

Frequencies

GnomAD3 genomes AF: 0.000624 AC: 94 AN: 150678 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000596

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.000483

GnomAD2 exomes AF: 0.00126 AC: 236 AN: 187348 AF XY: 0.00107

Gnomad AFR exome AF: 0.00319

Gnomad AMR exome AF: 0.00267

Gnomad ASJ exome AF: 0.000942

Gnomad EAS exome AF: 0.00150

Gnomad FIN exome AF: 0.000496

Gnomad NFE exome AF: 0.000782

Gnomad OTH exome AF: 0.000959

GnomAD4 exome AF: 0.000878 AC: 1195 AN: 1360382 Hom.: 0 Cov.: 30 AF XY: 0.000912 AC XY: 615 AN XY: 674520

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00252 AC: 75 AN: 29816

American (AMR) AF: 0.00150 AC: 50 AN: 33294

Ashkenazi Jewish (ASJ) AF: 0.000909 AC: 21 AN: 23100

East Asian (EAS) AF: 0.000830 AC: 31 AN: 37336

South Asian (SAS) AF: 0.00202 AC: 151 AN: 74810

European-Finnish (FIN) AF: 0.000879 AC: 44 AN: 50066

Middle Eastern (MID) AF: 0.000940 AC: 5 AN: 5318

European-Non Finnish (NFE) AF: 0.000713 AC: 749 AN: 1050976

Other (OTH) AF: 0.00124 AC: 69 AN: 55666

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000623 AC: 94 AN: 150784 Hom.: 0 Cov.: 32 AF XY: 0.000530 AC XY: 39 AN XY: 73618

African (AFR) AF: 0.00192 AC: 79 AN: 41172

American (AMR) AF: 0.000595 AC: 9 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.000389 AC: 2 AN: 5146

South Asian (SAS) AF: 0.000210 AC: 1 AN: 4768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67566

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00362 Hom.: 0

Bravo AF: 0.000748

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 23 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs541344421; hg19: chr1-63091085;