chr6-83124760-G-A

Position:

• chr6-83124760-G-A

Variant summary

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

The NM_015018.4(DOP1A):​c.1396G>A​(p.Glu466Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 4.07

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]

ACMG classification

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/exons	MANE	UniProt
DOP1A	NM_015018.4	c.1396G>A	p.Glu466Lys	missense_variant	13/39	ENST00000349129.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOP1A	ENST00000349129.7	c.1396G>A	p.Glu466Lys	missense_variant	13/39	1	NM_015018.4	P4
DOP1A	ENST00000369739.7	c.1369G>A	p.Glu457Lys	missense_variant	12/39	1		A1
DOP1A	ENST00000237163.9	c.1369G>A	p.Glu457Lys	missense_variant	13/40	5		A1
DOP1A	ENST00000604380.1	c.178G>A	p.Glu60Lys	missense_variant	2/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.1369G>A (p.E457K) 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 1369, causing the glutamic acid (E) at amino acid position 457 to be replaced by a lysine (K). 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	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;.
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.30	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.26	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.70	.;P;.
Vest4		0.81
MutPred		0.40		.;Gain of ubiquitination at E466 (P = 0.0085);.;
MVP		0.082
MPC		0.39
ClinPred		0.64	D
GERP RS		5.7
Varity_R		0.20
gMVP		0.34

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: rs1776885681; hg19: chr6-83834479;