6-83138565-C-T

Variant names:

• chr6-83138565-C-T
• NM_015018.4:c.4523C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015018.4(DOP1A):​c.4523C>T​(p.Ala1508Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DOP1A NM_015018.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

Genes affected

DOP1A (HGNC:21194): (DOP1 leucine zipper like protein A) Predicted to be involved in Golgi to endosome transport and endoplasmic reticulum organization. Predicted to be located in Golgi membrane. Predicted to be active in endosome and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

DOP1A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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=0.20418444).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOP1A	NM_015018.4	c.4523C>T	p.Ala1508Val	missense_variant	Exon 21 of 39	ENST00000349129.7	NP_055833.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DOP1A	ENST00000349129.7	c.4523C>T	p.Ala1508Val	missense_variant	Exon 21 of 39	1	NM_015018.4	ENSP00000195654.3
DOP1A	ENST00000369739.7	c.4496C>T	p.Ala1499Val	missense_variant	Exon 20 of 39	1		ENSP00000358754.3
DOP1A	ENST00000237163.9	c.4496C>T	p.Ala1499Val	missense_variant	Exon 21 of 40	5		ENSP00000237163.6
DOP1A	ENST00000484282.1	n.890C>T		non_coding_transcript_exon_variant	Exon 1 of 21	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4496C>T (p.A1499V) alteration is located in exon 21 (coding exon 19) of the DOPEY1 gene. This alteration results from a C to T substitution at nucleotide position 4496, causing the alanine (A) at amino acid position 1499 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L;.
PhyloP100		7.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.0	.;N;.
REVEL	Benign	0.11
Sift	Uncertain	0.010	.;D;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.40	.;B;.
Vest4		0.21
MutPred		0.22		.;Gain of methylation at K1509 (P = 0.04);.;
MVP		0.068
MPC		0.26
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.22
gMVP		0.57
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

hg19: chr6-83848284;