Genetic Variant DOP1A:p.Leu540Val (chr6-83125632-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_015018.4(DOP1A):c.1618C>G(p.Leu540Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., 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: 7.57

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DOP1A	NM_015018.4 link	c.1618C>G	p.Leu540Val	missense_variant	Exon 15 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.1618C>G	p.Leu540Val	missense_variant	Exon 15 of 39	1	NM_015018.4	ENSP00000195654.3	Q5JWR5
DOP1A	ENST00000369739.7 link	c.1591C>G	p.Leu531Val	missense_variant	Exon 14 of 39	1		ENSP00000358754.3	Q5TA12
DOP1A	ENST00000237163.9 link	c.1591C>G	p.Leu531Val	missense_variant	Exon 15 of 40	5		ENSP00000237163.6	Q5TA12
DOP1A	ENST00000604380.1 link	c.367C>G	p.Leu123Val	missense_variant	Exon 3 of 4	5		ENSP00000474846.1	S4R3Y1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251150

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

6.84e-7

AC:

AN:

1461582

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1591C>G (p.L531V) alteration is located in exon 15 (coding exon 13) of the DOPEY1 gene. This alteration results from a C to G substitution at nucleotide position 1591, causing the leucine (L) at amino acid position 531 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

Uncertain

0.54

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.062

.;T;.

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;.

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.48

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

.;L;.

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.6

.;D;.

REVEL

Benign

0.20

Sift

Benign

0.33

.;T;.

Sift4G

Uncertain

0.032

D;D;D

Polyphen

0.028

.;B;.

Vest4

0.77

MVP

0.20

MPC

0.31

ClinPred

0.79

GERP RS

5.2

Varity_R

0.53

gMVP

0.66

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