1-155325611-C-T

Variant names:

• chr1-155325611-C-T
• rs1651290708
• ENST00000490373:c.-321C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000490373(RUSC1):​c.-321C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RUSC1 ENST00000490373 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.71

Genes affected

RUSC1 (HGNC:17153): (RUN and SH3 domain containing 1) Predicted to enable actin binding activity. Involved in protein polyubiquitination. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34845418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RUSC1	NM_001105203.2	c.1753C>T	p.Arg585Cys	missense_variant	Exon 6 of 10	ENST00000368352.10	NP_001098673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RUSC1	ENST00000368352.10	c.1753C>T	p.Arg585Cys	missense_variant	Exon 6 of 10	2	NM_001105203.2	ENSP00000357336.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460490 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726586

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

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

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1753C>T (p.R585C) alteration is located in exon 6 (coding exon 5) of the RUSC1 gene. This alteration results from a C to T substitution at nucleotide position 1753, causing the arginine (R) at amino acid position 585 to be replaced by a cysteine (C). 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	0.099
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T;T;.;T;.;.;.
Eigen	Benign	-0.0030
Eigen_PC	Benign	-0.056
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;.;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L;.;.;.;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.1	D;D;.;D;.;D;.;D
REVEL	Benign	0.19
Sift	Uncertain	0.0050	D;D;.;D;.;D;.;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D
Polyphen		0.99, 0.99	.;D;.;.;.;D;.;D
Vest4		0.33
MutPred		0.59		Loss of MoRF binding (P = 0.0089);Loss of MoRF binding (P = 0.0089);.;.;.;.;.;.;
MVP		0.50
MPC		1.0
ClinPred		0.98	D
GERP RS		3.4
Varity_R		0.49
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1651290708; hg19: chr1-155295402;