chr1-62578974-C-A

Variant names:

• chr1-62578974-C-A
• rs79716948
• NM_001367561.1:c.1872-8G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001367561.1(DOCK7):​c.1872-8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 1,193,442 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.015 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0062 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DOCK7 NM_001367561.1 splice_region, intron
• Scores: Splicing: ADA: 0.000009257
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.69
• Publications: 3 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 -4 ACMG points.

• PM2: Variant has high frequency in the AMR (0.0186) population. However there is too low homozygotes in high coverage region: (expected more than 11, got 0).
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-62578974-C-A is Benign according to our data. Variant chr1-62578974-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 475131.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK7	NM_001367561.1	c.1872-8G>T		splice_region_variant, intron_variant	Intron 16 of 49	ENST00000635253.2	NP_001354490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK7	ENST00000635253.2	c.1872-8G>T		splice_region_variant, intron_variant	Intron 16 of 49	5	NM_001367561.1	ENSP00000489124.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 1229 AN: 79662 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0169

Gnomad AMI AF: 0.0427

Gnomad AMR AF: 0.0113

Gnomad ASJ AF: 0.00740

Gnomad EAS AF: 0.0133

Gnomad SAS AF: 0.00727

Gnomad FIN AF: 0.0283

Gnomad MID AF: 0.0128

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0116

GnomAD2 exomes AF: 0.0209 AC: 2190 AN: 104672 AF XY: 0.0217

Gnomad AFR exome AF: 0.0114

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0223

Gnomad EAS exome AF: 0.0136

Gnomad FIN exome AF: 0.0740

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0209

GnomAD4 exome AF: 0.00618 AC: 7372 AN: 1193442 Hom.: 0 Cov.: 27 AF XY: 0.00711 AC XY: 4177 AN XY: 587184

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

African (AFR) AF: 0.00341 AC: 85 AN: 24924

American (AMR) AF: 0.0202 AC: 416 AN: 20604

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 242 AN: 18770

East Asian (EAS) AF: 0.00677 AC: 214 AN: 31616

South Asian (SAS) AF: 0.0182 AC: 879 AN: 48304

European-Finnish (FIN) AF: 0.0697 AC: 2963 AN: 42526

Middle Eastern (MID) AF: 0.00860 AC: 32 AN: 3720

European-Non Finnish (NFE) AF: 0.00244 AC: 2329 AN: 954318

Other (OTH) AF: 0.00436 AC: 212 AN: 48660

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0155 AC: 1234 AN: 79692 Hom.: 0 Cov.: 23 AF XY: 0.0162 AC XY: 615 AN XY: 38028

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

African (AFR) AF: 0.0170 AC: 337 AN: 19832

American (AMR) AF: 0.0113 AC: 89 AN: 7894

Ashkenazi Jewish (ASJ) AF: 0.00740 AC: 17 AN: 2298

East Asian (EAS) AF: 0.0134 AC: 36 AN: 2686

South Asian (SAS) AF: 0.00768 AC: 21 AN: 2736

European-Finnish (FIN) AF: 0.0283 AC: 125 AN: 4416

Middle Eastern (MID) AF: 0.0135 AC: 2 AN: 148

European-Non Finnish (NFE) AF: 0.0151 AC: 575 AN: 38136

Other (OTH) AF: 0.0125 AC: 14 AN: 1124

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 23 Benign:1

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.85
DANN	Benign	0.44
PhyloP100		-1.7
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000093
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.070		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: rs79716948; hg19: chr1-63044645; COSMIC: COSV52020047;