10-16764464-G-T

Position:

• chr10-16764464-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012425.4(RSU1):​c.207C>A​(p.Asn69Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: RSU1 NM_012425.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RSU1	NM_012425.4	c.207C>A	p.Asn69Lys	missense_variant	4/9	ENST00000345264.10	NP_036557.1
RSU1	NM_152724.3	c.48C>A	p.Asn16Lys	missense_variant	3/8		NP_689937.2
RSU1	XM_047425617.1	c.207C>A	p.Asn69Lys	missense_variant	3/7		XP_047281573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RSU1	ENST00000345264.10	c.207C>A	p.Asn69Lys	missense_variant	4/9	1	NM_012425.4	ENSP00000339521	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 30, 2024

The c.207C>A (p.N69K) alteration is located in exon 4 (coding exon 3) of the RSU1 gene. This alteration results from a C to A substitution at nucleotide position 207, causing the asparagine (N) at amino acid position 69 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	0.99
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.2	D;D;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D;D;.
Sift4G	Uncertain	0.032	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.90
MutPred		0.52		Gain of ubiquitination at N69 (P = 0.0276);Gain of ubiquitination at N69 (P = 0.0276);.;
MVP		0.66
MPC		0.96
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.88
gMVP		0.75

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: rs1251036959; hg19: chr10-16806463;