rs2074130

Variant names:

• chr7-111847042-C-A
• rs2074130
• NM_001363540.2:c.2558G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-111847042-C-A
• chr7-111847042-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001363540.2(DOCK4):​c.2558G>T​(p.Arg853Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R853H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DOCK4 NM_001363540.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.53

Genes affected

DOCK4 (HGNC:19192): (dedicator of cytokinesis 4) This gene is a member of the dedicator of cytokinesis (DOCK) family and encodes a protein with a DHR-1 (CZH-1) domain, a DHR-2 (CZH-2) domain and an SH3 domain. This membrane-associated, cytoplasmic protein functions as a guanine nucleotide exchange factor and is involved in regulation of adherens junctions between cells. Mutations in this gene have been associated with ovarian, prostate, glioma, and colorectal cancers. Alternatively spliced variants which encode different protein isoforms have been described, but only one has been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOCK4	NM_001363540.2	c.2558G>T	p.Arg853Leu	missense_variant	Exon 24 of 53	ENST00000428084.6	NP_001350469.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOCK4	ENST00000428084.6	c.2558G>T	p.Arg853Leu	missense_variant	Exon 24 of 53	5	NM_001363540.2	ENSP00000410746.1
DOCK4	ENST00000437633.6	c.2558G>T	p.Arg853Leu	missense_variant	Exon 24 of 52	1		ENSP00000404179.1
DOCK4	ENST00000423057.6	c.911G>T	p.Arg304Leu	missense_variant	Exon 8 of 36	1		ENSP00000412834.1
DOCK4	ENST00000445943.5	c.2519G>T	p.Arg840Leu	missense_variant	Exon 23 of 53	5		ENSP00000397412.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.8	L;L;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.3	D;D;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.024	D;D;.
Sift4G	Benign	0.094	T;T;T
Polyphen		0.45	.;B;.
Vest4		0.68
MutPred		0.52		Loss of MoRF binding (P = 0.0468);Loss of MoRF binding (P = 0.0468);.;
MVP		0.90
MPC		0.58
ClinPred		0.92	D
GERP RS		6.0
Varity_R		0.43
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs2074130; hg19: chr7-111487098; COSMIC: COSV70233661;