rs140107023

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001330311.2(DVL1):c.1366A>G(p.Thr456Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,612,314 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 12 hom. )

Consequence

DVL1
NM_001330311.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7O:1

Conservation

PhyloP100: -1.14

Publications

6 publications found

Variant links:

Genes affected

DVL1 (HGNC:3084): (dishevelled segment polarity protein 1) DVL1, the human homolog of the Drosophila dishevelled gene (dsh) encodes a cytoplasmic phosphoprotein that regulates cell proliferation, acting as a transducer molecule for developmental processes, including segmentation and neuroblast specification. DVL1 is a candidate gene for neuroblastomatous transformation. The Schwartz-Jampel syndrome and Charcot-Marie-Tooth disease type 2A have been mapped to the same region as DVL1. The phenotypes of these diseases may be consistent with defects which might be expected from aberrant expression of a DVL gene during development. [provided by RefSeq, Jul 2008]

DVL1 Gene-Disease associations (from GenCC):

autosomal dominant Robinow syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal dominant Robinow syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DVL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009426951).

BP6

Variant 1-1338410-T-C is Benign according to our data. Variant chr1-1338410-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 445553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 309 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330311.2. 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
	DVL1	NM_001330311.2	MANE Select	c.1366A>G	p.Thr456Ala	missense	Exon 13 of 15	NP_001317240.1	O14640-1
	DVL1	NM_004421.3		c.1291A>G	p.Thr431Ala	missense	Exon 13 of 15	NP_004412.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DVL1	ENST00000378888.10	TSL:5 MANE Select	c.1366A>G	p.Thr456Ala	missense	Exon 13 of 15	ENSP00000368166.5	O14640-1
DVL1	ENST00000378891.9	TSL:1	c.1291A>G	p.Thr431Ala	missense	Exon 13 of 15	ENSP00000368169.5	O14640-2
DVL1	ENST00000874577.1		c.1531A>G	p.Thr511Ala	missense	Exon 13 of 15	ENSP00000544636.1

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

311

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00768

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00384

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00210

AC:

522

AN:

248966

AF XY:

0.00205

show subpopulations

Gnomad AFR exome

AF:

0.000561

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.000201

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00167

Gnomad NFE exome

AF:

0.00387

Gnomad OTH exome

AF:

0.000822

GnomAD4 exome

AF:

0.00333

AC:

4860

AN:

1460020

Hom.:

Cov.:

AF XY:

0.00327

AC XY:

2372

AN XY:

726276

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33472

American (AMR)

AF:

0.000313

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0000766

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.00132

AC:

114

AN:

86240

European-Finnish (FIN)

AF:

0.00190

AC:

AN:

52096

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00403

AC:

4480

AN:

1111626

Other (OTH)

AF:

0.00222

AC:

134

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

349

699

1048

1398

1747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

170

340

510

680

850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00203

AC:

309

AN:

152294

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

135

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41554

American (AMR)

AF:

0.000196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00382

AC:

260

AN:

68008

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00251

Hom.:

Bravo

AF:

0.00202

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00338

AC:

ExAC

AF:

0.00236

AC:

286

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00322

EpiControl

AF:

0.00332

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Autosomal dominant Robinow syndrome 2;C4551475:Autosomal dominant Robinow syndrome 1 (1)

DVL1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.29

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.37

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.46

M_CAP

Benign

0.0098

MetaRNN

Benign

0.0094

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

PhyloP100

-1.1

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.3

REVEL

Benign

0.029

Sift

Benign

0.47

Sift4G

Benign

0.71

Polyphen

0.057

Vest4

0.24

MVP

0.49

MPC

0.081

ClinPred

0.0051

GERP RS

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.055

gMVP

0.43

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over