rs140107023

Positions:

• chr1-1338410-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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. 15/21 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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -1.14

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 445553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 309 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DVL1	NM_001330311.2	c.1366A>G	p.Thr456Ala	missense_variant	13/15	ENST00000378888.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DVL1	ENST00000378888.10	c.1366A>G	p.Thr456Ala	missense_variant	13/15	5	NM_001330311.2	P3

Frequencies

GnomAD3 genomes AF: 0.00204 AC: 311 AN: 152176 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.00210 AC: 522 AN: 248966 Hom.: 0 AF XY: 0.00205 AC XY: 277 AN XY: 135220

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 SAS exome AF: 0.000915

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.: 12 Cov.: 38 AF XY: 0.00327 AC XY: 2372 AN XY: 726276

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.00190

Gnomad4 NFE exome AF: 0.00403

Gnomad4 OTH exome AF: 0.00222

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.00181 AC XY: 135 AN XY: 74464

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00382

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00260 Hom.: 0

Bravo AF: 0.00202

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00338 AC: 29

ExAC AF: 0.00236 AC: 286

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00322

EpiControl AF: 0.00332

ClinVar

Significance: Likely benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 20, 2017	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Likely benign and reported on 01-23-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DVL1: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2020	- -

DVL1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 04, 2022

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). -

Autosomal dominant Robinow syndrome 2;C4551475:Autosomal dominant Robinow syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.29
DANN	Benign	0.73
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.46	T;T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.0094	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.93	D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.3	N;N;.;.
REVEL	Benign	0.029
Sift	Benign	0.47	T;T;.;.
Sift4G	Benign	0.71	T;T;T;T
Polyphen		0.057	B;B;.;.
Vest4		0.24
MVP		0.49
MPC		0.081
ClinPred		0.0051	T
GERP RS		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.43

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

LitVar

Other links and lift over

dbSNP: rs140107023; hg19: chr1-1273790; COSMIC: COSV59562657; COSMIC: COSV59562657;