1-1336201-G-A

Variant names:

• chr1-1336201-G-A
• rs781175326
• NM_001330311.2:c.2029C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PP3_Moderate BP6_Moderate BS2

The NM_001330311.2(DVL1):​c.2029C>T​(p.Arg677Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000371 in 1,564,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R677H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: DVL1 NM_001330311.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.21

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845
• BP6: Variant 1-1336201-G-A is Benign according to our data. Variant chr1-1336201-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1357912.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DVL1	NM_001330311.2	c.2029C>T	p.Arg677Cys	missense_variant	Exon 15 of 15	ENST00000378888.10	NP_001317240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DVL1	ENST00000378888.10	c.2029C>T	p.Arg677Cys	missense_variant	Exon 15 of 15	5	NM_001330311.2	ENSP00000368166.5
DVL1	ENST00000378891.9	c.1954C>T	p.Arg652Cys	missense_variant	Exon 15 of 15	1		ENSP00000368169.5
DVL1	ENST00000632445.1	c.*342C>T		downstream_gene_variant		5		ENSP00000488888.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152200 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000301 AC: 5 AN: 166160 AF XY: 0.0000329

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000581

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000361 AC: 51 AN: 1412468 Hom.: 0 Cov.: 31 AF XY: 0.0000372 AC XY: 26 AN XY: 699626

Gnomad4 AFR exome AF: 0.000152 AC: 5 AN: 32830

Gnomad4 AMR exome AF: 0.0000254 AC: 1 AN: 39394

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25486

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 37844

Gnomad4 SAS exome AF: 0.0000244 AC: 2 AN: 81870

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 37900

Gnomad4 NFE exome AF: 0.0000375 AC: 41 AN: 1092584

Gnomad4 Remaining exome AF: 0.0000340 AC: 2 AN: 58836

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152200 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

Gnomad4 AFR AF: 0.000145 AC: 0.000144739 AN: 0.000144739

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000147 AC: 0.0000147007 AN: 0.0000147007

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000383 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.00000862 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	.;M;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.3	D;D;.
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.81
MVP		0.87
MPC		0.11
ClinPred		0.95	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.67
gMVP		0.74
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs781175326; hg19: chr1-1271581;