Genetic Variant DVL1:p.Arg593Gly (chr1-1336453-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001330311.2(DVL1):c.1777C>G(p.Arg593Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000705 in 1,419,370 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. 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. R593W) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

DVL1
NM_001330311.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.99

Publications

0 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:

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ACMG classification

Classification was made for transcript

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=0.15303674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DVL1	NM_001330311.2 link	c.1777C>G	p.Arg593Gly	missense_variant	Exon 15 of 15	ENST00000378888.10	NP_001317240.1	O14640-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DVL1	ENST00000378888.10 link	c.1777C>G	p.Arg593Gly	missense_variant	Exon 15 of 15	5	NM_001330311.2	ENSP00000368166.5	O14640-1
DVL1	ENST00000378891.9 link	c.1702C>G	p.Arg568Gly	missense_variant	Exon 15 of 15	1		ENSP00000368169.5	O14640-2
DVL1	ENST00000632445.1 link	c.*90C>G		3_prime_UTR_variant	Exon 6 of 6	5		ENSP00000488888.1	A0A0J9YYK1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1419370

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31700

American (AMR)

AF:

0.00

AC:

AN:

39824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24372

East Asian (EAS)

AF:

0.00

AC:

AN:

38740

South Asian (SAS)

AF:

0.00

AC:

AN:

82268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39300

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5546

European-Non Finnish (NFE)

AF:

9.10e-7

AC:

AN:

1098646

Other (OTH)

AF:

0.00

AC:

AN:

58974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.23

.;T;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.63

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.71

T;D;D

M_CAP

Benign

0.056

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.81

.;L;.

PhyloP100

4.0

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.69

N;N;.

REVEL

Benign

0.065

Sift

Benign

0.51

T;T;.

Sift4G

Benign

0.42

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.14

MutPred

0.25

.;Loss of helix (P = 0.0167);.;

MVP

0.76

MPC

0.11

ClinPred

0.16

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.10

gMVP

0.31

Mutation Taster

=93/7

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over