3-138162095-C-T

Variant names:

• chr3-138162095-C-T
• rs2042910240
• NM_016216.4:c.1429G>A

Variant summary

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

The NM_016216.4(DBR1):​c.1429G>A​(p.Val477Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DBR1 NM_016216.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09

Genes affected

DBR1 (HGNC:15594): (debranching RNA lariats 1) The protein encoded by this gene is an RNA lariat debranching enzyme that hydrolyzes 2'-5' prime branched phosphodiester bonds. The encoded protein specifically targets the bonds at the branch point of excised lariat intron RNA, converting them to linear molecules that are then degraded. This protein may also be involved in retroviral replication. [provided by RefSeq, Nov 2011]

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=0.21221104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DBR1	NM_016216.4	c.1429G>A	p.Val477Ile	missense_variant	Exon 8 of 8	ENST00000260803.9	NP_057300.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DBR1	ENST00000260803.9	c.1429G>A	p.Val477Ile	missense_variant	Exon 8 of 8	1	NM_016216.4	ENSP00000260803.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461892 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 09, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1429G>A (p.V477I) alteration is located in exon 8 (coding exon 8) of the DBR1 gene. This alteration results from a G to A substitution at nucleotide position 1429, causing the valine (V) at amino acid position 477 to be replaced by an isoleucine (I). 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	0.081
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.10
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.088
Sift	Benign	0.13	T
Sift4G	Benign	0.19	T
Polyphen		0.99	D
Vest4		0.062
MutPred		0.17		Loss of catalytic residue at V477 (P = 0.0122);
MVP		0.39
MPC		0.22
ClinPred		0.37	T
GERP RS		4.7
Varity_R		0.047
gMVP		0.099

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: rs2042910240; hg19: chr3-137880937;