Genetic Variant RUSC1:p.Pro114Ala (chr1-155322113-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001105203.2(RUSC1):c.340C>G(p.Pro114Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000633 in 1,611,412 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: 𝑓 0.00029 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

RUSC1
NM_001105203.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.94

Publications

0 publications found

Variant links:

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]

RUSC1 links:

RUSC1-AS1 (HGNC:26680): (RUSC1 antisense RNA 1)

RUSC1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.049967438).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001105203.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUSC1	NM_001105203.2	MANE Select	c.340C>G	p.Pro114Ala	missense	Exon 2 of 10	NP_001098673.1	Q9BVN2-1
RUSC1	NM_001105204.2		c.340C>G	p.Pro114Ala	missense	Exon 2 of 10	NP_001098674.1	Q9BVN2-4
RUSC1-AS1	NR_145424.1		n.294+130G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RUSC1	ENST00000368352.10	TSL:2 MANE Select	c.340C>G	p.Pro114Ala	missense	Exon 2 of 10	ENSP00000357336.5	Q9BVN2-1
RUSC1-AS1	ENST00000450199.2	TSL:1	n.264-418G>C		intron	N/A
RUSC1	ENST00000696599.1		c.340C>G	p.Pro114Ala	missense	Exon 2 of 11	ENSP00000512744.1	A0A8Q3SIT1

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000527

AC:

AN:

246708

AF XY:

0.0000224

show subpopulations

Gnomad AFR exome

AF:

0.000776

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000398

AC:

AN:

1459070

Hom.:

Cov.:

AF XY:

0.0000345

AC XY:

AN XY:

725540

show subpopulations

African (AFR)

AF:

0.00150

AC:

AN:

33430

American (AMR)

AF:

0.00

AC:

AN:

44494

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25888

East Asian (EAS)

AF:

0.00

AC:

AN:

39656

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85980

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53338

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110292

Other (OTH)

AF:

0.0000996

AC:

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000289

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

41584

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000454

Hom.:

Bravo

AF:

0.000351

ESP6500AA

AF:

0.00122

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000744

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.082

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.81

M_CAP

Benign

0.018

MetaRNN

Benign

0.050

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

PhyloP100

1.9

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.9

REVEL

Benign

0.094

Sift

Benign

0.030

Sift4G

Benign

0.10

Polyphen

0.98

Vest4

0.32

MVP

0.44

MPC

1.7

ClinPred

0.14

GERP RS

4.7

Varity_R

0.11

gMVP

0.13

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over