Genetic Variant DOP1A:p.Asp481Asn (chr6-83124805-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_015018.4(DOP1A):c.1441G>A(p.Asp481Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,150 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DOP1A
NM_015018.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.19

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.801

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOP1A	NM_015018.4 link	c.1441G>A	p.Asp481Asn	missense_variant	Exon 13 of 39	ENST00000349129.7	NP_055833.2	Q5JWR5B2RWN9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DOP1A	ENST00000349129.7 link	c.1441G>A	p.Asp481Asn	missense_variant	Exon 13 of 39	1	NM_015018.4	ENSP00000195654.3	Q5JWR5
DOP1A	ENST00000369739.7 link	c.1414G>A	p.Asp472Asn	missense_variant	Exon 12 of 39	1		ENSP00000358754.3	Q5TA12
DOP1A	ENST00000237163.9 link	c.1414G>A	p.Asp472Asn	missense_variant	Exon 13 of 40	5		ENSP00000237163.6	Q5TA12
DOP1A	ENST00000604380.1 link	c.220G>A	p.Asp74Asn	missense_variant	Exon 2 of 4	5		ENSP00000474846.1	S4R3Y1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249862

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135012

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726338

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1414G>A (p.D472N) alteration is located in exon 13 (coding exon 11) of the DOPEY1 gene. This alteration results from a G to A substitution at nucleotide position 1414, causing the aspartic acid (D) at amino acid position 472 to be replaced by an asparagine (N). 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

Pathogenic

0.75

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.43

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

.;T;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;.

M_CAP

Benign

0.040

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.7

.;M;.

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.010

D;D;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

1.0

.;D;.

Vest4

0.75

MutPred

0.69

.;Loss of helix (P = 0.028);.;

MVP

0.32

MPC

0.84

ClinPred

0.98

GERP RS

5.4

Varity_R

0.53

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over