21-36200371-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001320714.2(DOP1B):c.361G>T(p.Val121Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,458,436 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: 0.000016 (0 hom.)
• Consequence: DOP1B NM_001320714.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.39

Genes affected

DOP1B (HGNC:1291): (DOP1 leucine zipper like protein B) Involved in cognition. Located in early endosome membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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, 0.775

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DOP1B	NM_001320714.2	c.361G>T	p.Val121Leu	missense_variant	4/37	ENST00000691173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DOP1B	ENST00000691173.1	c.361G>T	p.Val121Leu	missense_variant	4/37		NM_001320714.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000444 AC: 11 AN: 247622 Hom.: 0 AF XY: 0.0000746 AC XY: 10 AN XY: 134030

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000364

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1458436 Hom.: 0 Cov.: 30 AF XY: 0.0000276 AC XY: 20 AN XY: 725554

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: 0.000279

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000577 AC: 7

Asia WGS AF: 0.00231 AC: 8 AN: 3478

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

Oct 27, 2021

The c.361G>T (p.V121L) alteration is located in exon 4 (coding exon 3) of the DOPEY2 gene. This alteration results from a G to T substitution at nucleotide position 361, causing the valine (V) at amino acid position 121 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	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.77	D;D
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.012	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		1.0	.;D
Vest4		0.80
MutPred		0.64		Loss of methylation at R122 (P = 0.2398);Loss of methylation at R122 (P = 0.2398);
MVP		0.61
MPC		0.72
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.66
gMVP		0.71

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: rs746027069; hg19: chr21-37572669;