8-25184952-C-T

Variant names:

• chr8-25184952-G-T
• rs1801392673
• NM_024940.8:c.43+1G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024940.8(DOCK5):​c.43+1G>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000781 in 1,280,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: DOCK5 NM_024940.8 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.26
• Publications: 0 publications found

Genes affected

DOCK5 (HGNC:23476): (dedicator of cytokinesis 5) This gene encodes a member of the dedicator of cytokinesis protein family. Members of this family act as guanine nucleotide exchange factors for small Rho family G proteins. The protein encoded by this gene is thought to associate with adaptors CRK and CRKL, and function in regulation of intestinal epithelial cell spreading and migration on collagen IV. Similar proteins in mouse and zebrafish also function in myoblast fusion. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024940.8. 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
	DOCK5	NM_024940.8	MANE Select	c.43+1G>T		splice_donor intron	N/A	NP_079216.4
	DOCK5	NM_001322810.2		c.43+1G>T		splice_donor intron	N/A	NP_001309739.1	B9A015

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK5	ENST00000276440.12	TSL:1 MANE Select	c.43+1G>T		splice_donor intron	N/A	ENSP00000276440.7	Q9H7D0-1
	DOCK5	ENST00000481100.5	TSL:1	c.43+1G>T		splice_donor intron	N/A	ENSP00000429737.1	Q9H7D0-2
	DOCK5	ENST00000410074.5	TSL:2	c.43+1G>T		splice_donor intron	N/A	ENSP00000387036.1	B9A015

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.81e-7 AC: 1 AN: 1280180 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 631956

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

African (AFR) AF: 0.00 AC: 0 AN: 26772

American (AMR) AF: 0.00 AC: 0 AN: 24134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20090

East Asian (EAS) AF: 0.00 AC: 0 AN: 30740

South Asian (SAS) AF: 0.00 AC: 0 AN: 60942

European-Finnish (FIN) AF: 0.0000220 AC: 1 AN: 45482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4648

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1016264

Other (OTH) AF: 0.00 AC: 0 AN: 51108

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.36	N
PhyloP100		2.3
PromoterAI		-0.53	Under-expression
Mutation Taster		=10/90	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: -1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1801392673;

hg19: chr8-25042467;