Genetic Variant RSU1:p.Asn96Lys (chr10-16754983-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_012425.4(RSU1):c.288C>G(p.Asn96Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000618 in 1,455,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

RSU1
NM_012425.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.696

Publications

1 publications found

Variant links:

Genes affected

RSU1 (HGNC:10464): (Ras suppressor protein 1) This gene encodes a protein that is involved in the Ras signal transduction pathway, growth inhibition, and nerve-growth factor induced differentiation processes, as determined in mouse and human cell line studies. In mouse, the encoded protein was initially isolated based on its ability to inhibit v-Ras transformation. Multiple alternatively spliced transcript variants for this gene have been reported; one of these variants was found only in glioma tumors. [provided by RefSeq, Jul 2008]

RSU1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSU1	NM_012425.4 link	c.288C>G	p.Asn96Lys	missense_variant	Exon 5 of 9	ENST00000345264.10	NP_036557.1	Q15404-1
RSU1	NM_152724.3 link	c.129C>G	p.Asn43Lys	missense_variant	Exon 4 of 8		NP_689937.2	Q15404-2
RSU1	XM_047425617.1 link	c.288C>G	p.Asn96Lys	missense_variant	Exon 4 of 7		XP_047281573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSU1	ENST00000345264.10 link	c.288C>G	p.Asn96Lys	missense_variant	Exon 5 of 9	1	NM_012425.4	ENSP00000339521.5		Q15404-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249428

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000618

AC:

AN:

1455956

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

724578

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33120

American (AMR)

AF:

0.00

AC:

AN:

44446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26058

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.00

AC:

AN:

85850

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5102

European-Non Finnish (NFE)

AF:

0.00000722

AC:

AN:

1108288

Other (OTH)

AF:

0.0000166

AC:

AN:

60150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000549

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.288C>G (p.N96K) alteration is located in exon 5 (coding exon 4) of the RSU1 gene. This alteration results from a C to G substitution at nucleotide position 288, causing the asparagine (N) at amino acid position 96 to be replaced by a lysine (K). 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

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;T;.

Eigen

Benign

-0.068

Eigen_PC

Benign

-0.31

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.91

D;D;D

MetaSVM

Uncertain

-0.16

MutationAssessor

Pathogenic

3.8

H;H;.

PhyloP100

0.70

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.7

D;D;.

REVEL

Uncertain

0.48

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.0020

D;D;.

Polyphen

1.0

D;D;.

Vest4

0.96

MutPred

0.72

Gain of MoRF binding (P = 0.0217);Gain of MoRF binding (P = 0.0217);.;

MVP

0.63

MPC

0.93

ClinPred

1.0

GERP RS

-4.5

Varity_R

0.79

gMVP

0.89

Mutation Taster

=32/68

disease causing

(source)

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

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10-16754983-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over