1-1340424-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_001330311.2(DVL1):c.685C>G(p.Arg229Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,612,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R229P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

DVL1
NM_001330311.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 2.06

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.079295814).

BP6

Variant 1-1340424-G-C is Benign according to our data. Variant chr1-1340424-G-C is described in ClinVar as Benign. ClinVar VariationId is 599454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 57 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DVL1	NM_001330311.2	MANE Select	c.685C>G	p.Arg229Gly	missense	Exon 6 of 15	NP_001317240.1
	DVL1	NM_004421.3		c.685C>G	p.Arg229Gly	missense	Exon 6 of 15	NP_004412.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DVL1	ENST00000378888.10	TSL:5 MANE Select	c.685C>G	p.Arg229Gly	missense	Exon 6 of 15	ENSP00000368166.5
DVL1	ENST00000378891.9	TSL:1	c.685C>G	p.Arg229Gly	missense	Exon 6 of 15	ENSP00000368169.5
DVL1	ENST00000633096.1	TSL:4	n.-59C>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.000374

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000720

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000303

AC:

AN:

244568

AF XY:

0.000331

show subpopulations

Gnomad AFR exome

AF:

0.000193

Gnomad AMR exome

AF:

0.0000588

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000623

Gnomad NFE exome

AF:

0.000482

Gnomad OTH exome

AF:

0.000506

GnomAD4 exome

AF:

0.000407

AC:

594

AN:

1460048

Hom.:

Cov.:

AF XY:

0.000406

AC XY:

295

AN XY:

726232

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33464

American (AMR)

AF:

0.0000450

AC:

AN:

44430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26052

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86068

European-Finnish (FIN)

AF:

0.000586

AC:

AN:

52934

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000483

AC:

537

AN:

1111414

Other (OTH)

AF:

0.000282

AC:

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000374

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41464

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000720

AC:

AN:

68044

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000359

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000289

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Nov 15, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, BS2, BP1, BP4; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, is a missense alteration in a gene for which primarily truncating variants are known to cause disease, and is predicted to be tolerated by multiple functional prediction tools.

DVL1-related disorder

Benign:1

May 10, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

not provided

Benign:1

Nov 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.010

MetaRNN

Benign

0.079

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.6

PhyloP100

2.1

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.9

REVEL

Benign

0.026

Sift

Benign

0.088

Sift4G

Benign

0.13

Polyphen

0.23

Vest4

0.50

MVP

0.74

MPC

0.13

ClinPred

0.021

GERP RS

2.7

PromoterAI

-0.042

Neutral

(source)

Varity_R

0.097

gMVP

0.23

Mutation Taster

=77/23

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over