rs377719435

Variant names:

• chr1-62476049-T-C
• rs377719435
• NM_001367561.1:c.5724+18A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-62476049-T-C
• chr1-62476049-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001367561.1(DOCK7):​c.5724+18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000193 in 1,607,320 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (4 hom.)
• Consequence: DOCK7 NM_001367561.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.82
• Publications: 0 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-62476049-T-C is Benign according to our data. Variant chr1-62476049-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445979.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000201 (292/1454980) while in subpopulation SAS AF = 0.00246 (211/85778). AF 95% confidence interval is 0.00219. There are 4 homozygotes in GnomAdExome4. There are 194 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK7	NM_001367561.1	MANE Select	c.5724+18A>G		intron	N/A	NP_001354490.1
	DOCK7	NM_001330614.2		c.5697+18A>G		intron	N/A	NP_001317543.1
	DOCK7	NM_001271999.2		c.5691+18A>G		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.5724+18A>G		intron	N/A	ENSP00000489124.1
	DOCK7	ENST00000454575.6	TSL:1	c.5691+18A>G		intron	N/A	ENSP00000413583.2
	DOCK7	ENST00000251157.10	TSL:5	c.5697+18A>G		intron	N/A	ENSP00000251157.6

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000371 AC: 92 AN: 248130 AF XY: 0.000492

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000468

Gnomad NFE exome AF: 0.0000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000201 AC: 292 AN: 1454980 Hom.: 4 Cov.: 29 AF XY: 0.000268 AC XY: 194 AN XY: 724262

African (AFR) AF: 0.0000301 AC: 1 AN: 33206

American (AMR) AF: 0.00 AC: 0 AN: 44144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25948

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00246 AC: 211 AN: 85778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53082

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5740

European-Non Finnish (NFE) AF: 0.0000560 AC: 62 AN: 1107354

Other (OTH) AF: 0.000183 AC: 11 AN: 60094

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74506

African (AFR) AF: 0.0000240 AC: 1 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4830

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

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000491

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Developmental and epileptic encephalopathy, 23 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.20
DANN	Benign	0.46
PhyloP100		-1.8
Mutation Taster		=100/0	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: rs377719435; hg19: chr1-62941720;