6-83129323-C-T

Position:

• chr6-83129323-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015018.4(DOP1A):​c.2156C>T​(p.Ser719Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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: 0.746

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06898439).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOP1A	NM_015018.4	c.2156C>T	p.Ser719Leu	missense_variant	16/39	ENST00000349129.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOP1A	ENST00000349129.7	c.2156C>T	p.Ser719Leu	missense_variant	16/39	1	NM_015018.4	P4
DOP1A	ENST00000369739.7	c.2129C>T	p.Ser710Leu	missense_variant	15/39	1		A1
DOP1A	ENST00000237163.9	c.2129C>T	p.Ser710Leu	missense_variant	16/40	5		A1

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

Aug 17, 2022

The c.2129C>T (p.S710L) alteration is located in exon 16 (coding exon 14) of the DOPEY1 gene. This alteration results from a C to T substitution at nucleotide position 2129, causing the serine (S) at amino acid position 710 to be replaced by a leucine (L). 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	0.069
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.95
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.87	D;D;.
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.28	T
REVEL	Benign	0.074
Sift4G	Benign	0.66	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.14
MutPred		0.29		.;Gain of catalytic residue at S719 (P = 5e-04);.;
MVP		0.043
MPC		0.23
ClinPred		0.084	T
GERP RS		3.9
Varity_R		0.093
gMVP		0.28

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: rs1777668033; hg19: chr6-83839042;