NM_144658.4:c.697C>T

Variant names:

• chrX-118566008-C-T
• rs763088906
• NM_144658.4:c.697C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144658.4(DOCK11):​c.697C>T​(p.Pro233Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,976 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: DOCK11 NM_144658.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77
• Publications: 1 publications found

Genes affected

DOCK11 (HGNC:23483): (dedicator of cytokinesis 11) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in several processes, including marginal zone B cell differentiation; positive regulation of GTPase activity; and positive regulation of filopodium assembly. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

DOCK11 Gene-Disease associations (from GenCC):

• autoinflammatory disease, multisystem, with immune dysregulation, X-linked

  Inheritance: XL Classification: STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18884033).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144658.4. 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
	DOCK11	NM_144658.4	MANE Select	c.697C>T	p.Pro233Ser	missense	Exon 8 of 53	NP_653259.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DOCK11	ENST00000276202.9	TSL:1 MANE Select	c.697C>T	p.Pro233Ser	missense	Exon 8 of 53	ENSP00000276202.7	Q5JSL3
	DOCK11	ENST00000276204.10	TSL:5	c.697C>T	p.Pro233Ser	missense	Exon 8 of 53	ENSP00000276204.6	A6NIW2
	DOCK11	ENST00000966546.1		c.697C>T	p.Pro233Ser	missense	Exon 8 of 53	ENSP00000636605.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000549 AC: 1 AN: 182070 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000725

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096976 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362444

⚠️ 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: 26365

American (AMR) AF: 0.00 AC: 0 AN: 35108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30179

South Asian (SAS) AF: 0.00 AC: 0 AN: 53859

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841401

Other (OTH) AF: 0.00 AC: 0 AN: 46044

⚠️ 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.: 23

ExAC AF: 0.00000824 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	0.13
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	23
DANN	Benign	0.89
DEOGEN2	Benign	0.084	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.35	N
PhyloP100		1.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	0.30	N
REVEL	Benign	0.21
Sift	Benign	0.70	T
Sift4G	Benign	0.55	T
Polyphen		0.23	B
Vest4		0.10
MutPred		0.48		Gain of MoRF binding (P = 0.0633)
MVP		0.59
MPC		1.1
ClinPred		0.22	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.83
Mutation Taster		=75/25	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: rs763088906; hg19: chrX-117699971;