7-111811914-G-A

Variant names:

• chr7-111811914-G-A
• rs957373527
• NM_001363540.2:c.2966C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001363540.2(DOCK4):​c.2966C>T​(p.Ala989Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000263 in 152,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. A989G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DOCK4 NM_001363540.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.20
• Publications: 0 publications found

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]

DOCK4-AS1 (HGNC:40876): (DOCK4 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37992185).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363540.2. 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
	DOCK4	NM_001363540.2	MANE Select	c.2966C>T	p.Ala989Val	missense	Exon 28 of 53	NP_001350469.1	Q8N1I0-3
	DOCK4	NM_014705.4		c.2966C>T	p.Ala989Val	missense	Exon 28 of 52	NP_055520.3
	DOCK4-AS1	NR_103806.1		n.109+3301G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK4	ENST00000428084.6	TSL:5 MANE Select	c.2966C>T	p.Ala989Val	missense	Exon 28 of 53	ENSP00000410746.1	Q8N1I0-3
	DOCK4	ENST00000437633.6	TSL:1	c.2966C>T	p.Ala989Val	missense	Exon 28 of 52	ENSP00000404179.1	Q8N1I0-1
	DOCK4	ENST00000423057.6	TSL:1	c.1319C>T	p.Ala440Val	missense	Exon 12 of 36	ENSP00000412834.1	H0Y7H7

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1377300 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 680242

African (AFR) AF: 0.00 AC: 0 AN: 31008

American (AMR) AF: 0.00 AC: 0 AN: 34846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24806

East Asian (EAS) AF: 0.00 AC: 0 AN: 35454

South Asian (SAS) AF: 0.00 AC: 0 AN: 78384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1060896

Other (OTH) AF: 0.00 AC: 0 AN: 57130

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74290

African (AFR) AF: 0.0000483 AC: 2 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.86	L
PhyloP100		6.2
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Benign	0.68	T
Sift4G	Benign	0.32	T
Polyphen		0.096	B
Vest4		0.44
MutPred		0.33		Gain of methylation at K992 (P = 0.0787)
MVP		0.38
MPC		0.72
ClinPred		0.94	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.35
Mutation Taster		=79/21	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: rs957373527; hg19: chr7-111451970;