3-197675081-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_014687.4(RUBCN):c.2856A>G(p.Ser952=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,613,250 control chromosomes in the GnomAD database, including 21,120 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (7425 hom., cov: 32)
  • Exomes 𝑓: 0.11 (13695 hom.)
• Consequence: RUBCN NM_014687.4 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -7.15

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-197675081-T-C is Benign according to our data. Variant chr3-197675081-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 129379.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-7.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RUBCN	NM_014687.4	c.2856A>G	p.Ser952=	synonymous_variant	20/20	ENST00000296343.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RUBCN	ENST00000296343.10	c.2856A>G	p.Ser952=	synonymous_variant	20/20	1	NM_014687.4	P1
RUBCN	ENST00000707076.1	c.2973A>G	p.Ser991=	synonymous_variant	22/22
RUBCN	ENST00000413360.5	c.2742A>G	p.Ser914=	synonymous_variant	19/19	5
RUBCN	ENST00000273582.9	c.2721A>G	p.Ser907=	synonymous_variant	21/21	5

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34759 AN: 152012 Hom.: 7395 Cov.: 32

Gnomad AFR AF: 0.569

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.128

Gnomad ASJ AF: 0.0914

Gnomad EAS AF: 0.0457

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0572

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.121 AC: 29489 AN: 244102 Hom.: 3497 AF XY: 0.116 AC XY: 15457 AN XY: 133492

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.0746

Gnomad ASJ exome AF: 0.0997

Gnomad EAS exome AF: 0.0400

Gnomad SAS exome AF: 0.121

Gnomad FIN exome AF: 0.0642

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.112 AC: 164083 AN: 1461122 Hom.: 13695 Cov.: 33 AF XY: 0.111 AC XY: 80630 AN XY: 726868

Gnomad4 AFR exome AF: 0.594

Gnomad4 AMR exome AF: 0.0786

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.0647

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.0635

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.229 AC: 34845 AN: 152128 Hom.: 7425 Cov.: 32 AF XY: 0.221 AC XY: 16458 AN XY: 74394

Gnomad4 AFR AF: 0.569

Gnomad4 AMR AF: 0.128

Gnomad4 ASJ AF: 0.0914

Gnomad4 EAS AF: 0.0454

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.0572

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.170

Alfa AF: 0.134 Hom.: 837

Bravo AF: 0.249

Asia WGS AF: 0.141 AC: 491 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.109

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.17
Dann	Benign	0.46

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: rs28562770; hg19: chr3-197401952; COSMIC: COSV56376936; COSMIC: COSV56376936;