rs758373500

Variant names:

• chr7-111728659-T-C
• rs758373500
• NM_001363540.2:c.5543A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-111728659-T-C
• chr7-111728659-T-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001363540.2(DOCK4):​c.5543A>G​(p.Asn1848Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1848D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DOCK4 NM_001363540.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72
• 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]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20402688).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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.5543A>G	p.Asn1848Ser	missense	Exon 53 of 53	NP_001350469.1	Q8N1I0-3
	DOCK4	NM_014705.4		c.5516A>G	p.Asn1839Ser	missense	Exon 52 of 52	NP_055520.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK4	ENST00000428084.6	TSL:5 MANE Select	c.5543A>G	p.Asn1848Ser	missense	Exon 53 of 53	ENSP00000410746.1	Q8N1I0-3
	DOCK4	ENST00000437633.6	TSL:1	c.5516A>G	p.Asn1839Ser	missense	Exon 52 of 52	ENSP00000404179.1	Q8N1I0-1
	DOCK4	ENST00000423057.6	TSL:1	c.3782A>G	p.Asn1261Ser	missense	Exon 36 of 36	ENSP00000412834.1	H0Y7H7

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151450 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461674 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727120

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111864

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151450 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73934

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

African (AFR) AF: 0.00 AC: 0 AN: 41142

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10510

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67864

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ 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: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		5.7
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.027
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.56	T
Polyphen		0.43	B
Vest4		0.32
MutPred		0.23		Gain of glycosylation at N1839 (P = 0.0135)
MVP		0.48
MPC		0.087
ClinPred		0.41	T
GERP RS		4.4
Varity_R		0.14
gMVP		0.26
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs758373500; hg19: chr7-111368715;