3-197675039-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_014687.4(RUBCN):c.2898C>T(p.Ala966=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00275 in 1,612,738 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (5 hom.)
• Consequence: RUBCN NM_014687.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0930

Genes affected

RUBCN (HGNC:28991): (rubicon autophagy regulator) The protein encoded by this gene is a negative regulator of autophagy and endocytic trafficking and controls endosome maturation. This protein contains two conserved domains, an N-terminal RUN domain and a C-terminal DUF4206 domain. The RUN domain is involved in Ras-like GTPase signaling, and the DUF4206 domain contains a diacylglycerol (DAG) binding-like motif. Mutation in this gene results in deletion of the DAG binding-like motif and causes a recessive ataxia. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 3-197675039-G-A is Benign according to our data. Variant chr3-197675039-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 791392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-197675039-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.093 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUBCN	NM_014687.4	c.2898C>T	p.Ala966=	synonymous_variant	20/20	ENST00000296343.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUBCN	ENST00000296343.10	c.2898C>T	p.Ala966=	synonymous_variant	20/20	1	NM_014687.4	P1
RUBCN	ENST00000707076.1	c.3015C>T	p.Ala1005=	synonymous_variant	22/22
RUBCN	ENST00000413360.5	c.2784C>T	p.Ala928=	synonymous_variant	19/19	5
RUBCN	ENST00000273582.9	c.2763C>T	p.Ala921=	synonymous_variant	21/21	5

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 276 AN: 152190 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00139 AC: 337 AN: 242880 Hom.: 1 AF XY: 0.00148 AC XY: 197 AN XY: 132950

Gnomad AFR exome AF: 0.00109

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.000605

Gnomad EAS exome AF: 0.0000562

Gnomad SAS exome AF: 0.00193

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00151

GnomAD4 exome AF: 0.00284 AC: 4151 AN: 1460430 Hom.: 5 Cov.: 32 AF XY: 0.00287 AC XY: 2085 AN XY: 726496

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00175

Gnomad4 FIN exome AF: 0.000153

Gnomad4 NFE exome AF: 0.00336

Gnomad4 OTH exome AF: 0.00312

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74480

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00259

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00227 Hom.: 1

Bravo AF: 0.00214

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00296

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	RUBCN: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	9.1
Dann	Benign	0.77

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: rs202195282; hg19: chr3-197401910;